Biological aging and the development of chronic diseases are strongly influenced by interactions between environmental factors and the epigenome, rather than genetic predisposition alone. Vitamin D₃ is a key modulator of immune function, acting via the vitamin D receptor (VDR) to regulate gene expression and cellular differentiation. However, clinical outcomes of vitamin D supplementation are highly variable between individuals, suggesting fundamental differences in biological responsiveness. This lecture introduces the vitamin D response index as a clinically relevant concept to stratify individuals according to their molecular responsiveness to vitamin D and to link this variability to immune competence, healthy aging, and disease risk. Data are derived from human intervention studies with controlled vitamin D₃ supplementation, in which peripheral blood immune cells were analyzed longitudinally for changes in gene expression and chromatin accessibility. These molecular readouts were integrated with clinical and physiological parameters to assess interindividual variability in response. Vitamin D₃ supplementation induces broad and dynamic changes in immune cell function, reflected by alterations in the expression of genes involved in inflammation, metabolism, and cellular stress responses. Individuals can be reproducibly classified into high, mid, and low responders based on their vitamin D response index. Importantly, low responders exhibit attenuated molecular and functional responses despite similar supplementation, suggesting a reduced capacity to benefit from standard dosing regimens. These differences provide a mechanistic explanation for inconsistent clinical trial outcomes and indicate that uniform supplementation strategies may be insufficient for optimal disease prevention. The vitamin D response index enables clinically meaningful stratification of individuals and highlights the need to move beyond one-size-fits-all recommendations. Assessing individual responsiveness may improve the efficacy of vitamin D interventions in reducing the risk of immune-related and age-associated diseases. In conclusion, precision nutrition must shift from population-based recommendations to mechanism-guided, individualized interventions to effectively support healthy aging and disease prevention.