Exposure to chronic stress, either repeated severe acute or moderate sustained stress, is one of the strongest risk factors for the development of psychopathologies such as post-traumatic stress disorder and depression. Chronic stress is linked with several lasting biological consequences, particularly to the stress endocrine system but also affecting intermediate phenotypes such as brain structure and function, immune function, and behavior. Although genetic predisposition confers a proportion of the risk, the most relevant molecular mechanisms determining those susceptible and resilient to the effects of stress and trauma may be epigenetic. Epigenetics refers to the mechanisms that regulate genomic information by dynamically changing the patterns of transcription and translation of genes. Mounting evidence from preclinical rodent and clinical population studies strongly support that epigenetic modifications can occur in response to traumatic and chronic stress. Here, we discuss this literature examining stress-induced epigenetic changes in preclinical models and clinical cohorts of stress and trauma occurring early in life or in adulthood. We highlight that a complex relationship between the timing of environmental stressors and genetic predispositions likely mediate the response to chronic stress over time, and that a better understanding of epigenetic changes is needed by further investigations in longitudinal and postmortem brain clinical cohorts.