The incidence of inflammatory bowel disease (IBD) has risen in the past decades and has emerged as a global health issue. IBD is characterized by chronic inflammation of the gastrointestinal tract. There is compelling evidence for the role of biological sex in IBD epidemiology, pathophysiology, disease progression, symptoms and extra-intestinal diseases. IBD disease course, management and therapies differ between men and women, yet there is a paucity of analysis of sex as a factor. This Review discusses the known influence of sex-linked genetic factors, hormones and hormone receptors in IBD incidence, prevalence, disease burden and clinical manifestation. Furthermore, we review the mechanisms underlying these sex-dependent effects on the dysregulation of gastrointestinal mucosal immunity (immune, epithelial barrier and microbiota) in IBD. To support the progressive inclusion of sex in the study of IBD, we summarize the current standard research methodology that should be implemented to investigate sex as a biological variable in IBD studies. Enhanced comprehension of the influence of sex in IBD pathophysiology will advance the development of targeted therapies and improve patient care.