Obesity is associated with both increased cancer incidence and progression in multiple tumour types, and is estimated to contribute to up to 20% of cancer-related deaths. These associations are driven, in part, by metabolic and inflammatory changes in adipose tissue that disrupt physiological homeostasis both within local tissues and systemically. However, the mechanisms underlying the obesity-cancer relationship are poorly understood. In this Review, we describe how the adipose tissue microenvironment (ATME) evolves during body-weight gain, and how these changes might influence tumour initiation and progression. We focus on multiple facets of ATME physiology, including inflammation, vascularity and fibrosis, and discuss therapeutic interventions that have the potential to normalize the ATME, which might be translationally relevant for cancer prevention and therapy. Given that the prevalence of obesity is increasing on an international scale, translational research initiatives are urgently needed to provide mechanistic explanations for the obesity-cancer relationship, and how to best identify high-risk individuals without relying on crude measures, such as BMI.