Selective serotonin re-uptake inhibitors (SSRIs) are front-line pharmacotherapies in the treatment of major depressive disorder (MDD), a disorder characterized by a persistent low mood, anhedonia and feelings of worthlessness. Since their formulation over 40 years ago, there have been several conflicting studies exploring the efficacy of these highly prevalent drugs. The nature of their therapeutic effect has also remained elusive, with several hypothesises pertaining to neurotransmitter and endocrine modulation proposed. While the medications are better tolerated than their predecessors, the tricyclic antidepressant family (TCAs), the side effect profile of SSRIs is not insubstantial and novel cases have highlighted adverse effects enduring past the cessation of drug treatment. Data gathered from clinical practice also highlights that the prevalence of these side effects is often underestimated, leading to patient frustration and non-compliance. This report will seek to outline the rise of SSRI usage in the last half century while exploring possible avenues of pharmacotherapeutic action, with a particular focus on the side effect profile of these drugs.