While the musculoskeletal system is not typically the first considered in the context of sex-biased biology, emerging evidence shows that it exhibits profound sex-based differences in both structure and function. This chapter explores these differences in orthopedic tissues, with a focus on how biomaterial systems can be used to interrogate cellular mechanisms and deliver sex hormones in a spatially and temporally controlled manner to promote regeneration and homeostasis. Further, these biomaterials can be used to determine how structural and mechanical cues from the tissue microenvironment drive cell behavior and can be capitalized on for applications in cell migration and regeneration, considering sex as a biological variable for more personalized regenerative engineering strategies. While advancements have been made in biomaterial design for hormone release and sex-specific regeneration, there are several limitations that still exist to ensure scientific conclusions are sound and biomaterial devices are rigorous and reproducible. The main caveats are complexities with sex hormones in cell culture media confounding the impact of hormone dosing in controlled studies, the wide variance in hormone levels from person to person and daily/month/yearly within a single person, and adequately powered study designs to confidently contribute differences to biological sex and not donor variability. The goal is to highlight opportunities in biomaterial design that support discovery and therapeutic innovation for sex-informed approaches after injury and to promote lifetime musculoskeletal health.