Antidepressants were first developed serendipitously 60 years ago and gave rise to the monoamine hypothesis of depression and antidepressant action which has persisted in various forms ever since. Although we have made huge strides in our understanding of the pharmacology of antidepressants, and in the neuroscience of depression, our current antidepressants have changed little since the original drugs. In this chapter I first review some controversies in the use of antidepressant drugs including whether they actually work, and then go on to describe the current state of our clinical use of antidepressants, looking both at the principles and practice of treatment and reviewing the evidence for efficacy, tolerability and safety in acute and sequenced treatments. I finally briefly consider future directions and the aspiration of developing more effective antidepressants.