Stroke represents a major health problem in the United States and most European and Asian countries. Depression is probably the most common and serious emotional disorder following stroke. Post-stroke depression (PSD) has frequently been overlooked and left untreated. Prevention of PSD or successful intervention in the early phase may prevent premature deaths as well as facilitate rehabilitation, reduce costs, and improve quality of life. Stroke is clearly a risk factor for depression, and recent evidence suggests that depression increases the risk for stroke, although the mechanisms by which depression leads to stroke remain to be clarified. Once PSD has developed, numerous studies have documented its adverse effect on cognitive recovery, physical recovery, and mortality. Taken together, these studies support the necessity of identifying and treating this condition.