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Abstract Vitamin D is responsible for regulation of calcium and phosphate metabolism and maintaining a healthy mineralized skeleton. It is also known as an immunomodulatory hormone. Experimental studies have shown that 1,25-dihydroxyvitamin D, the active form of vitamin D, exerts immunologic activities on multiple components of the innate and adaptive immune system as well as endothelial membrane stability. Association between low levels of serum 25-hydroxyvitamin D and increased risk of developing several immune-related diseases and disorders, including psoriasis, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, tuberculosis, sepsis, respiratory infection, and COVID-19, has been observed. Accordingly, a number of clinical trials aiming to determine the efficacy of administration of vitamin D and its metabolites for treatment of these diseases have been conducted with variable outcomes. Interestingly, recent evidence suggests that some individuals might benefit from vitamin D more or less than others as high inter-individual difference in broad gene expression in human peripheral blood mononuclear cells in response to vitamin D supplementation has been observed. Although it is still debatable what level of serum 25-hydroxyvitamin D is optimal, it is advisable to increase vitamin D intake and have sensible sunlight exposure to maintain serum 25-hydroxyvitamin D at least 30 ng/mL (75 nmol/L), and preferably at 40–60 ng/mL (100–150 nmol/L) to achieve the optimal overall health benefits of vitamin D. keywords vitamin D; immune function; 25-hydroxyvitamin D; 1,25-dihydroxyvitamin D; immunomodulation; autoimmune disorders; infectious diseases; lymphocytes; monocytes; macrophages; multiple sclerosis; type 1 diabetes; inflammation; endothelial membrane stability 7. Conclusions Vitamin D plays an essential undisputed role in the maintenance of calcium, phosphate, and bone metabolism. There is compelling evidence that immune cells convert 25(OH)D to 1,25(OH)2D in an unregulated manner and are dependent on the circulating levels of 25(OH)D to be at least 30 ng/mL (75 nmol/L) [4,17,18]. Once a 1,25(OH)2D is produced, it acts in an autocrine and paracrine fashion to modulate the innate and adaptive immune systems. There is also some evidence that vitamin D itself may modulate immune function in a non-genomic manner by stabilizing endothelial membranes [36]. Most of the evidence, to date, suggests that maintenance of a healthy vitamin D status is important for modulating the body’s immune function. Low serum levels of 25(OH)D are associated with multiple immune-related diseases including autoimmune disorders and infectious diseases. There is less convincing evidence that vitamin D is an effective treatment strategy for autoimmune diseases and infectious diseases with a few exceptions documented in this review. Whether vitamin D therapy is effective as an adjunctive immunomodulatory agent for treatment of most diseases it is still controversial based on heterogeneous findings from the clinical trials. National and international programs should be instituted to educate the public about the health benefits of vitamin D and policies to fortify commonly consumed foods with vitamin D to reduce the risk of vitamin D deficiency during pregnancy, childhood, and in young and middle-aged adults when autoimmune disorders are most prevalent. In addition, improvement in vitamin D status from birth until death may help reduce the risk of infectious diseases such as influenza and COVID-19 that can have devastating consequences especially for the elderly. However, more investigation is needed to determine who would most benefit from vitamin D, and how much vitamin D is required for its maximum health benefit based on their individual vitamin D responsive profile. It is also unknown whether giving 1,25(OH)2D3 or one of its analogs is a reasonable approach for treating autoimmune disorders and infectious diseases. Blood levels of 1,25(OH)2D3 are tightly controlled and for good reason, i.e., any significant increase in circulating levels of 1,25(OH)2D will result in an increase in intestinal calcium absorption and, when uncontrolled, this causes hypercalciuria and ultimately hypercalcemia. It is more likely that the endogenous production of 1,25(OH)2D in the immune cells including monocytes and macrophages is what is required for vitamin D to have its immunomodulatory functions. Although most of the biologic effects of vitamin D have been related to its active metabolite there continues to be intriguing evidence that vitamin D itself may have its own biologic actions independent of its metabolism. Our hunter gatherer forefathers likely maintained serum vitamin D levels in the range of 10–50 ng/mL (25–125 nmol/L). This is supported by the observation that Maasai herders and Hadza tribesmen maintained serum 25(OH)D in the range of 40–60 ng/mL (100–150 nmol/L) [12,13]. To maintain these blood levels, a person would require ingesting approximately 4000–6000 IUs daily. This would therefore maintain circulating levels of vitamin D in the range of 20–40 ng/mL (50–100 nmol/L). The observation that in vitro vitamin D3 was much more effective than either 25(OH)D3 or 1,25(OH)2D3 in stabilizing endothelial membranes thereby reducing inflammation may help explain the interesting clinical observations that extremely high doses of vitamin D have been effective in treating or at least reducing symptoms of some autoimmune disorders including psoriasis, vitiligo, and multiple sclerosis [37,85]. The observation that children with congenital autosomal recessive ichthyosis and epidermolytic ichthyosis had a dramatic improvement in their skin disease when treated with 60,000 IUs of vitamin D once a day for 10 days adds strength to the argument that vitamin D itself may have its own important role in the maintenance of good health [199]. There are still open questions that need to be further investigated in order to take full advantage of the effect of vitamin D on the immune system for clinical practice. The bottom line is that there is no downside to increasing our intake of vitamin D to maintain serum 25(OH)D at at least 30 ng/mL (75 nmol/L), and preferably at 40–60 ng/mL (100–150 nmol/L) to achieve optimal overall health benefits of vitamin D. You can read the full paper at https://www.mdpi.com/2072-6643/12/7/2097/htm I take 5,000 units of Vitamin D per day. You should consult with your doc on how much you should take as their is a danger of taking too much.