Selective Serotonin reuptake inhibitors (SSRIs) have contributed to the major advances in the treatment of depression and other psychiatric diseases. This review summarises current knowledge concerning the SSRI class of drugs and discusses the importance of secondary pharmacology in the mechanism of action and effectiveness of these drugs. Particular attention is given to the emerging importance of the SSRI ‘plus’ approach: where the serotonin reuptake receptor inhibition of a drug is supplemented by one or more other receptor interactions either by the same drug or by a combination therapy. This area of research has shed light on the pharmacological mechanisms of SSRI therapy and has the therapeutic usefulness of serotonin reuptake inhibition, especially in the area of depression. There are many new emerging SSRI ‘plus’ drugs, which address the pharmacological and pharmacokinetic issues of current therapies and these, are discussed in detail.