Vitamin D has emerged as a pleiotropic regulator of human physiology, and recent work has revealed that it has several roles in control of human immune system function. Vitamin D was originally characterized for its role in calcium homeostasis, and the active form, 1,25-dihydroxyvitamin D (1,25D), can be produced in the kidney by 1α-hydroxylation of circulating 25-hydroxyvitamin D catalyzed by the enzyme CYP27B1. Renal CYP27B1 expression is regulated by calcium regulatory inputs, and 1,25D produced in the kidney was thought to function largely as an endocrine hormone. However, it is now clear that CYP27B1 is expressed in numerous tissues, and that 1,25D acts at several sites in the body in an intracrine or paracrine manner. In particular, both CYP27B1 and the vitamin D receptor (VDR) are expressed in several cell types in the immune system, where CYP27B1 production is controlled by a number of immune-specific inputs. Recent research has opened several windows on the molecular mechanisms by which 1,25D signaling regulates both innate and adaptive immune responses in humans. Moreover, intervention trials are beginning to provide evidence that vitamin D supplementation can bolster clinical responses to infection. This review will discuss recent developments in our understanding of how immune signaling controls local vitamin D metabolism and how, in turn, the 1,25D-bound VDR modulates immune system function. A particular emphasis will be placed on the interplay between vitamin D signaling and signaling through different classes of pattern recognition receptors in the production of antimicrobial peptides during innate immune responses to microbial infection.