Obesity is frequently associated with chronic inflammation, metabolic and vascular alterations which predispose to the development of the Metabolic Syndrome (MetS). However, the individual obesity-related risk for the MetS is not determined by increased fat mass alone. Heterogeneity of body composition, fat distribution and adipose tissue (AT) function may underly the variable risk to develop metabolic and cardiovascular diseases associated with increased body fat mass. Importantly, an inability to increase AT mass by adipocyte hyperplasia may lead to adipocyte hypertrophy and could induce dysfunction of adipose tissue characterized by decreased insulin sensitivity, hypoxia, increased parameters of intracellular stress, increased autophagy and apoptosis and tissue inflammation. As a result, adipocytes and other AT cells release signals (e.g. adipokines, cells, metabolites) resulting in a proinflammatory, diabetogenic and atherogenic serum profile. These adverse signals may contribute to further AT inflammation and secondary organ damage in target tissues such as liver, brain, endothelium, vasculature, endocrine organs and skeletal muscle. Recently, a specific adipocyte volume threshold has been shown to predict the risk for obesity-associated type 2 diabetes. Most likely, impaired adipocyte function is caused by genetic, behavioural and environmental factors which are not entirely understood. Elucidating the mechanisms of adipocyte dysfunction may lead to the identification of novel treatment targets for obesity and the MetS.