Depression is a world-wide health problem that currently affects approximately 16% of the population in the United States alone. As one of the most common psychiatric disorders, it can be quite debilitating, and is certainly a major financial burden. With current medications suffering from major shortcomings that include slow onset of action, poor efficacy, and unwanted side effects, the search for new and improved antidepressants is ever increasing. Many patients may seek complementary and alternative medicine (CAM) remedies to evade the financial burden, adverse effects, or because of cultural or religious beliefs. Thus these remedies offer a valuable resource for the discovery of new and improved antidepressant medications. This chapter provides an overview of the current knowledge state regarding a variety of natural products commonly used in depression. Herbal medicines discussed have been used in clinical trials for the treatment of mild to moderate depression states include the popular St. John’s wort, saffron, Rhodiola, lavender, Echium, and the Chinese formula banxia houpu. A comprehensive review of both clinical and preclinical aspects of each of the reviewed products is provided.