Epidemiologists have identified that depression will soon be the leading cause of disability throughout the world. To inform public health campaigns to reduce this problem, this paper summarizes current scientific knowledge about optimizing the potential of primary care settings to reduce disability by providing effective treatment for depression. To meet this challenge, primary care practices need to be re-engineered: 1) to conduct systematic screening programs to identify depressed patients, 2) to provide depressed patients initial evidence-based treatment, and 3) to monitor treatment adherence and symptom response in treated patients over 2 years. While additional research is needed in developing countries, preliminary evidence indicates that primary care practices re-engineered to improve depression management can make a substantial contribution to reducing depression-associated disability.