OBJECTIVE: Police, firefighters, dispatchers, and emergency medical technicians-collectively known as first responders-are a unique population frequently exposed to chronic, traumatic incidents. This exposure results in a high prevalence of PTSD, depression, and anxiety, posing a substantial public health concern. Genetic predispositions and epigenetic modifications that regulate gene expression are significant contributors to trauma-related pathologies. This systematic review aims to summarize current data on epigenetic and gene expression changes in first responders related to three post-trauma pathologies: PTSD, depression, and anxiety. We also explore genetic pathways across these disorders to identify potential commonalities and therapeutic targets. METHODS: Following PRISMA guidelines, databases were searched from July to October 2023, yielding 1103 studies, 12 of which met the inclusion criteria (total N = 6943). RESULTS: Of the included studies, 11 examined PTSD, consistently implicating stress-response genes, such as those in the hypothalamic-pituitary-adrenal axis (e.g., FKBP5, NR3C1), and genes related to inflammation and immune responses. Three studies focused on depression-related genetic biomarkers but reported no significant genome-wide methylation differences between responders with current versus no major depressive disorder (MDD). No studies addressed epigenetic or gene expression changes linked to anxiety. CONCLUSION: This review identified novel genes and pathways related to trauma as potential targets for future research and pharmacological therapy. It also highlights a significant gap in the literature, emphasizing the need for broader research to investigate the genetic underpinnings of trauma exposure in first responders, aiming to identify relevant pathways and therapeutic targets.