Depressive disorder is a common illness that affects millions of people worldwide and the patients often suffer from symptoms such as depressed mood, sleep disturbances, and suicidal ideation. Since the approval of fluoxetine in the United States nearly 20 years ago, the annual prescription of antidepressants has increased rapidly. However, despite the increasing number of new antidepressants introduced to the clinic, the quality of treatment still remains poor due to the delayed response or low efficacy often associated with these synthetic antidepressants. Thus, there have been a growing number of patients turning to alternative medicine treatments for a more effective cure. To date, one of the most frequently used and well-studied herbal preparation for mild and moderate depression is the extract of St Johns wort. However, recent report has indicated that drug interaction of this herb with other antidepressants may result in severe clinical consequences. Traditional Chinese medicine (TCM) has a long history of use in China with a proven record of high efficacy and low toxicity. It is also an excellent source of diverse and complex chemicals that possess a wide variety of biological activities. In recent years, TCM has received growing attention as an alternative or adjuvant therapy to Western medicine treatments and a large volume of efforts have been directed towards the identification of potential antidepressive phytomedicine from TCM. Potential TCM-derived therapeutics including herbal formulations, extracts, and individual active constituents have been evaluated with behavioral animal models and clinical studies. This article will review the recent development in the search for effective antidepressive therapeutics using TCM. Literatures published in Chinese will also be reviewed to include the recent advances in this area. Moreover, our group has been using a knowledge-based approach to identify active ingredients for the treatment of neurological disorders. The workflow of our approach will also be discussed.