In this review, we explore the potential drivers of heterogeneity in response to Vitamin D (VitD) therapy, such as bioavailability, sex-specific response, and autoimmune pathology, in those at risk for and diagnosed with T2DM. In addition, we propose distinct populations for future interventions with VitD. The literature concerning VitD supplementation in the prevention, treatment, and remission of type 2 diabetes mellitus (T2DM) spans decades, is complex, and is often contradictory with mixed findings upon intervention. By association, VitD status is powerfully predictive with deficient subjects reporting greater risk for T2DM, conversion to T2DM from prediabetes, and enhanced response to VitD therapy. Preclinical models strongly favor intervention with VitD owing to the pleiotropic influence of VitD on multiple systems. Additional research is crucial as there remain many questions unanswered that are related to VitD status and conditions such as T2DM. Future research must be conducted to better understand the potentially spurious relationships between VitD status, supplementation, sun exposure, health behaviors, and the diagnosis and management of T2DM. Public health practice can greatly benefit from a better understanding of the mechanisms by which we can reliably increase VitD status and how this can be used to develop education and improve health behaviors.