Many epidemiologic, observational and randomized human clinical trials have demonstrated beyond doubt the protective cardiovascular effects of omega-3 polyunsaturated fatty acids (PUFAs). Cardiac myocytes protection by omega-3 PUFAs involves several mechanisms which might have a synergistic effect. This review provides a summary of the in vitro and in vivo effects of omega-3 PUFAs on cardiac myocytes health and reports the outcome of a number of clinical trials in patients consuming omega-3 PUFAs.