Obesity is a chronic multisystem disease associated with increased morbidity and mortality. The increasing prevalence of obesity makes it a major healthcare challenge across both developed and developing countries. Traditional measures such as body mass index do not always identify individuals at increased risk of comorbidities, yet continue to be used in deciding who qualifies for weight loss treatment. A better understanding of how obesity is associated with comorbidities, in particular non-metabolic conditions, is needed to identify individuals at risk in order to prioritize treatment. For metabolic disorders such as type 2 diabetes (T2D), weight loss can prevent T2D in individuals with prediabetes. It can improve and reverse T2D if weight loss is achieved early in the course of the disease. However, access to effective weight loss treatments is a significant barrier to improved health for people with obesity. In the present paper, we review the rising prevalence of obesity and why it should be classed as a multisystem disease. We will discuss potential mechanisms underlying its association with various comorbidities and how these respond to treatment, with a particular focus on cardiometabolic disease, malignancy and mental health.