The global burden of depression is estimated over 300 million, which is equivalent to 4.4% of the world's population. However, it is reported that only 50% of patients receive some form of treatment and most individuals receiving conventional pharmacotherapy fail to achieve and sustain remission. Treatment-resistant depression (TRD) is defined as failure to achieve remission with two or more adequate antidepressants over a sufficient period of time. Treatment-resistant depression is estimated to occur in 10–30% of patients with major depression, and these patients need a variety of treatment strategies employed. Advances in genetic epidemiology have spurred research investigating the role genetics play in the pathophysiology of depression. Pharmacogenetic testing identifies mutations related to altered expression and functions of genes associated with antidepressant response. For this reason, genetic variants are considered theoretically optimal biomarkers to provide personalized antidepressant treatments and to reduce the proportion of patients who develop TRD. This review aims to understand the genetic mechanisms that contribute to the problem of TRD and the hurdles to its treatment in the context of the Indian population. We focus on the authors’ clinical experience in parallel with relevant research articles over the last two decades.