The global prevalence of obesity has been rising at an alarming rate, accompanied by an increase in both childhood and maternal obesity. The concept of metabolic programming is highly topical, and in this context, describes a predisposition of offspring of obese mothers to the development of obesity independent of environmental factors. Research published in this issue of Clinical Science conducted by Litzenburger and colleagues (Clin. Sci. (Lond.) (2020) 134, 921–939) have identified sex-dependent differences in metabolic programming and identify putative signaling pathways involved in the differential phenotype of adipose tissue between males and females. Delineating the distinction between metabolically healthy and unhealthy obesity is a topic of emerging interest, and the precise nature of adipocytes are key to pathogenesis, independent of adipose tissue volume.