An extensive number of different studies, from animal models to clinical and family studies, support the important role of genetic background and epigenetic factors, besides the effects of environmental milieu, on the variability of pain response. So far, precise mechanisms of pain perception and transmission in the central nervous system have not been fully understood. However, comprehensive data imply that a disinhibition and imbalance of the neurotransmitters serotonin and norepinephrine might play key roles. Both neurotransmitters have complex pathways, comprised of numerous receptors, autoreceptors, transporters and enzymes. Recently, it has been shown that clinically relevant inter-individual differences in pain perception and regulation are influenced by a tri-allelic polymorphism in the serotonin transporter gene. In the central nervous system there is another important group of proteins, neurotrophins, which regulate cell growth and survival, differentiation, apoptosis, and cytoskeleton restructuring. The dysregulation of brain-derived neurotrophic factors has been found in individuals with Traumatic Brain Injury and Posttraumatic Stress Disorder, with chronic pain as one of the common clinical features. Genomics has a promising potential to contribute to advances in the elucidation of pain mechanisms and control. With modern laboratory techniques that enable the identification of candidate genes by linkage mapping, whole-genome association, and single gene association studies, genes responsible for different pain disorders could be isolated in the near future. Knowledge of these genetic factors could further support another important issue – personalized medicine – that could improve the efficacy of pain management and lower adverse event profiles.