This paper develops the conceptual framework of “sex contextualism” for the study of sex-related variables in biomedical research. Sex contextualism offers an alternative to binary sex essentialist approaches to the study of sex as a biological variable. Specifically, sex contextualism recognizes the pluralism and context-specificity of operationalizations of ‘sex’ across experimental laboratory research. In light of recent policy mandates to consider sex as a biological variable, sex contextualism offers constructive guidance to biomedical researchers for attending to sex-related biological variation. As an alternative to and critique of biological binary sex essentialism, sex contextualism contributes to current debates in philosophy of biology, feminist science studies, and social ontology on the construction of categories of gender/sex differences in scientific research.