Functional and structural imaging studies of major depressive illness reported over the past decade are reviewed. It is concluded that while various prefrontal and temporal brain regions are often reported as being abnormal, interpretation of such findings is limited due to lack of understanding of normal function. This leads to a discussion of what is known of normal function. It is concluded that in animals, these brain regions correspond to the neural substrate for emotional learning, representation of the rewarding and aversive aspects of stimuli, and associated behavioral response. Imaging studies, which investigate reward based learning in humans appear consistent. Additionally however, these brain regions may be most active in healthy humans experiencing emotion. A large meta-analysis exploring this issue is discussed. The link between normal human emotions and reinforcers is then reviewed, followed by a discussion of the clinical features of depressive illness, in the light of the hypothesis that depressive illness is a disorder of emotional learning. Formal mathematical theories of emotional learning all include a predictive error term, formed by the difference between future predicted reward or punishment and the actual outcome. Extensive experimental evidence of the existence of predictive error signals in animals, and more recently in imaging studies of healthy humans, is reviewed. This is followed by a discussion of a study reporting abnormal predictive error signals in depressed patients, which tested the hypothesis that depressive illness is a disorder of emotional learning. Finally, existing diverse treatments for depressive illness are considered from the perspective of emotional learning mechanisms. A number of studies are suggested, to clarify understanding of the mechanisms of effective treatments for depressive illness.