Many studies show inverse relationships between the prevalence and severity of various clinical conditions and vitamin D status. Reverse causality may be expected for some of these due to alterations in organ function that may impact vitamin D metabolism and bioavailability. I will review conditions that affect three aspects of vitamin D metabolism: intestinal absorption, vitamin D binding protein (VDBP) function and renal metabolism. For each, I will review relevant guidelines and recommendations for patient and population health. Dietary vitamin D is absorbed incorporated in chylomicrons. Consequently, gastrointestinal (GI) conditions affecting fat absorption and chylomicron formation can lead to impaired vitamin D bioavailability. The hydroxylated form, 25 hydroxy vitamin D (25(OH)D) is absorbed into the portal vein independent of fat absorption and may provide an alternative to maintain vitamin D status in some GI conditions. All vitamin D metabolites are bound to VDBP, which has multiple functions. VDBP facilitates transportation and cellular uptake of vitamin D metabolites and elongates their half-life, through protection against hydroxylation into catabolic products. VDBP also plays a key role in scavenging of actin upon cellular damage and inflammation, which results in a sharp decrease in plasma VDBP concentrations. As a result, the free fraction of vitamin D metabolites increases and this is likely associated with increased hydroxylation into downstream metabolites, explaining the frequently observed decrease in vitamin D status in severely ill individuals. Further, the VDBP-actin complex plays a role in the activation of the innate immune response. Little is known about vitamin D requirements in severely ill and surgical patients and the evidence-base for specific recommendations is limited. The kidney has several roles in vitamin D metabolism: internalisation of VDBP-25(OH)D complex, hydroxylation of 25(OH)D into 1,25(OH)2 vitamin D (1,25(OH)2D) and into catabolic products and reabsorption of the VDBP-vitamin D metabolite complex from the glomerular filtrate. With renal impairment, 1,25(OH)2D concentrations gradually decrease and, depending on the location of kidney damage, VDBP and its bound metabolites may be lost in urine. Recommendations for the use of vitamin D, analogues or activated metabolites take these alterations into consideration and vary by stage of renal dysfunction. Specific guidance accounting for alterations in vitamin D requirements with many clinical conditions is lacking. This is partly due to the complexity and involvement of many organ systems in vitamin D metabolism. Understanding altered organ function and metabolism with clinical conditions is essential for management of vitamin D status and function.