There is substantial genetic and epidemiological evidence implicating vitamin D in the pathogenesis of many common diseases. A number of studies have sought to define an association for disease with sequence variation in the VDR gene, encoding the ligand-activated nuclear hormone receptor for vitamin D. The results of such studies have been difficult to replicate and are likely to need to account for specific environmental exposures. Here, we review recent work that has begun to study the interactions between VDR gene polymorphisms, vitamin D blood levels, and complex disease susceptibility, notably in the context of major clinical outcomes. We highlight the challenges moving forward in this area and its importance for effective clinical translation of current research.