The prevalence of obesity and related metabolic disorders is largely the result of poor dietary choices and excessive caloric intake. Consumption of palatable, energy-rich foods can lead to obesity and increase the risk of depression. Depression not only impairs the quality of life of obese individuals but also increases the associated risks of obesity and hinders motivation to seek out and adhere to weight loss strategies. In turn, certain forms of depression are closely linked with overeating, promoting an adverse cycle of depressed mood, comfort-food seeking and further weight gain. This chapter provides an overview of the metabolic, immune and neural processes that accompany increased adiposity and obesity and their impact on mood and the development of depression. In this context, potential treatments for the alleviation of depression co-morbid with obesity are discussed.