Personalized or precision medicine is a relatively new promising concept which is gaining momentum in all branches of medicine including psychiatry and neurology. Psychiatry and neurology are medical specialties dealing with diagnosis, prevention and treatment of brain disorders which are the main causes of years lived with disability worldwide as well as shortened life. Despite a huge progress in clinical psychopharmacology and neuropharmacology, the treatment outcome for many psychiatric disorders and neurologic diseases has remained unsatisfactory. With aging, comorbidities are more the rule, than an exception and may significantly influence on the final treatment outcome. Epigenetic modulation, resilience and life style are key determinants of the health and very important issues for understanding therapeutic mechanisms and responses. There is a hope that epigenetic profiling before treatment could be used in near future to increase the likelihood of good treatment response by selecting the appropriate medication. The aim of this paper is to offer an overview of the main aspects of epigenetic modulation, resilience and comorbidities and their role in developing the concept of personalized medicine. While waiting for more precise and reliable treatment guidelines it is possible to increase treatment effectiveness in psychiatry and neurology by enhancing individual resilience of patients and managing comorbidities properly.