The AMP-activated protein kinase (AMPK) system was first discovered 30 years ago. Since that time, knowledge of the diverse physiological functions of AMPK has grown rapidly and continues to evolve. Most recently, the observation that spontaneously occurring genetic mutations in the gamma regulatory subunits of AMPK give rise to a skeletal and cardiac muscle disease emphasizes the critical importance of AMPK in the maintenance of health and disease. The cardiac phenotype observed in humans harbouring genetic mutations in the gamma 2 regulatory subunit (PRKAG2) of AMPK is consistent with abnormal glycogen accumulation in the heart. The perturbation of AMPK activity induced by genetic mutations in PRKAG2 and the resultant effect on muscle cell glucose metabolism may be relevant to the issue of targeting AMPK in drug development for insulin-resistant diabetes mellitus.