Stressful life incidents often cause a predisposition for developing mental disorders such as major depressive disorder (MDD). Impaired neurocognitive and neuro-vegetative functions of the central nervous system are the hallmarks of this mental illness. Blunted responses from emotionally salient regions of the brain including cortex, hippocampus, and amygdala have been associated with MDD-related behavioral changes. Moreover, improper signal processing and neuronal atrophy were held responsible for the overall dysfunctionality of these vulnerable regions in the MDD brain. The prevalence of genetic susceptibility along with adverse environmental stimuli often makes the situation worse for MDD patients, leading to an increased risk of suicidal behavior and eventually death by suicide. Despite considerable efforts to understand the complex neurobiology associated with MDD and suicidal behavior, their pathological determinants remain mostly elusive. Recent research, however, has shown that epigenetic perturbations have a formidable impact on the etiopathogenesis of MDD. Understanding the neuroepigenetic nature of this mental disorder may provide opportunities to devise more effective treatment strategies. Moreover, this can potentially lead to identifying predictive biomarkers associated with suicide risk. The present chapter critically reviews studies pertaining to epigenetic signatures of MDD and suicide brain.