DNA methylation and chromatin modifications regulate gene expression and contribute to changes in brain transcriptomes underlying neurodevelopmental and psychiatric disorders. Clinical genetics and preclinical animal models highlight the crucial importance of the correct establishment of epigenetic marks during sensitive windows of development for normal brain function. On the same side of the coin, some of the concerned factors also appear engaged in the programming of experience-dependent long-term effects on mental health following exposure to relevant early-life events. Delineating the particular role of genetic variations in these players could provide new insights into the molecular basis of vulnerability and resilience and advance tailored therapies.