The vitamin D receptor (VDR) is a member of the large family of nuclear receptor transcription factors and specifically binds the micronutrient-derived hormone 1alpha,25(OH)2D3. A central endocrine role for this receptor in bone health was established at the beginning of the 20th century. Over the last 25 years, additional roles, perhaps through autocrine and paracrine mechanisms, have been established for VDR to regulate cell proliferation and differentiation, and more recently to exert immunomodulatory and antimicrobial functions. These findings, from in vitro and in vivo experiments, have generated considerable interest in targeting the VDR in multiple therapeutic settings. As with many potential therapeutics, it has also become clear that cells and tissues may also display de novo and acquired mechanisms of resistance to these actions. Consequently, a range of experimental and clinical options are being developed to bring about more targeted actions, overcome resistance and enhance efficacy of VDR-centred therapeutics.