Background Epidemiologists need tools to measure effects of gender , a complex concept originating in the social sciences which is not easily operationalized in the discipline. Our aim is to clarify useful concepts, measures, paths, effects, and analytical strategies to explore mechanisms of health difference between men and women. Methods We reviewed concepts to clarify their definitions and limitations for their translation into usable measures in Epidemiology. Then we conducted methodological research using a causal framework to propose methodologically appropriate strategies for measuring sex and gender effects in health. Results (1) Concepts and measures. We define gender as a set of norms prescribed to individuals according to their attributed-at-birth sex. G ender pressure creates a systemic gap, at population level, in behaviors, activities, experiences, etc., between men and women. A pragmatic individual measure of gender would correspond to the level at which an individual complies with a set of elements constituting femininity or masculinity in a given population, place and time. (2) Main analytical strategy. Defining and measuring gender are not sufficient to distinguish the effects of sex and gender on a health outcome. We should also think in terms of mechanisms, i.e., how the variables are linked together, to define appropriate analytical strategies. A causal framework can help us to conceptualize “sex” as a “parent” of a gender or gendered variable. This implies that we cannot interpret sex effects as sexed mechanisms, and that we can explore gendered mechanisms of sex-differences by mediation analyses. (3) Alternative strategy. Gender could also be directly examined as a mechanism, rather than through a variable representing its realization in the individual, by approaching it as an interaction between sex and social environment. Conclusions Both analytical strategies have limitations relative to the impossibility of reducing a complex concept to a single or a few measures, and of capturing the entire effect of the phenomenon of gender. However, these strategies could lead to more accurate analyses of the mechanisms underlying health differences between men and women.