Along with age and race, sex has historically been a core stratification and control variable in epidemiologic research. While in recent decades research guidelines and institutionalized requirements have incorporated an approach differentiating biological sex from social gender, neither sex nor gender is itself a unidimensional construct. The conflation of dimensions within and between sex and gender presents a validity issue wherein proxy measures are used for dimensions of interest, often without explicit acknowledgement or evaluation. Here, individual-level dimensions of sex and gender are outlined as a guide for epidemiologists, and 2 case studies are presented. The first case study demonstrates how unacknowledged use of a sex/gender proxy for a sexed dimension of interest (uterine status) resulted in decades of cancer research misestimating risks, racial disparities, and age trends. The second illustrates how a multidimensional sex and gender framework may be applied to strengthen research on coronavirus disease 2019 incidence, diagnosis, morbidity, and mortality. Considerations are outlined, including: 1) addressing the match between measures and theory, and explicitly acknowledging and evaluating proxy use; 2) improving measurement across dimensions and social ecological levels; 3) incorporating multidimensionality into research objectives; and 4) interpreting sex, gender, and their effects as biopsychosocial.