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Scientific research associations, funders, and publishers have recently introduced sex inclusion mandates requiring the use of male and female specimens in preclinical research designs and the analysis and reporting of data disaggregated by sex. However, it is not necessarily a simple matter to incorporate males and females in the same study design with the aim of detecting differences between them while following best practices for rigorous inference in laboratory science using model organisms. For example, if there are ways in which male and female variability might differ for the trait or procedure of interest, principles of sound experimental design may require larger numbers of organisms and observations to make valid inferences about the presence of a sex difference. This paper analyzes a current scientific debate over differences in variability between male and female laboratory rodents, and specifically over whether potential sources of sex-specific variability such as the estrous cycle, group housing, and body size constitute components of sex that should be measured. The variability debate surfaces the trade-offs between constructs of sex difference and similarity that face scientific researchers attempting to meet mandates to include both males and females in research design and report sex-specific results. This riddle of variability illuminates how laboratory researchers using model organisms must make contextual choices (Richardson 2022) at multiple decision points in order to stabilize sex as a biological variable in a particular research design. These judgments are informed by social and epistemic values and carry consequences for the validity, precision, and generalizability of claims of biological sex differences derived from preclinical research models.