Women are typically underrepresented in clinical trials, in part due to historical restrictions on female enrollment1,2, which has led to a knowledge gap. Without adequate representation, our understanding of how biological sex (chromosomes and anatomy) and gender (a social construct and internal sense of self)2 may influence the acquisition and pathogenesis of infectious diseases remains incomplete. But is consideration of sex and/or gender important in understanding microbial pathogenesis? For human immunodeficiency virus (HIV), notwithstanding the limits of the available research, decades of clinical and basic-science data provide a clear answer: sex and gender impact HIV pathogenesis3. Here, using HIV as the focus and including select examples from other diseases, I argue that sex and gender must be integrated into infectious disease research as a tool for discovery.