The decline in functional performance and restriction of adaptability represents the hallmark of skeletal muscle pathologies. The characteristic loss in muscle mass, coupled with a decrease in strength and force output, has been associated with a selective activation of apoptotic pathways and a general reduction in survival mechanisms. Aging and genetic diseases, such as muscular dystrophies, amyotrophic lateral sclerosis, cancer and AIDS, are characterized by alterations in metabolic and physiological parameters, progressive weakness in specific muscle groups, modulation in muscle-specific transcriptional mechanisms and persistent protein degradation. The inability to regenerate and repair the injured muscle is another serious complication in muscle pathologies. Tissue remodeling is therefore an important physiological process, which allows skeletal muscle to respond to environmental demands and to undergo adaptive changes in cytoarchitecture and protein composition, in response to a variety of stimuli. Alterations in extracellular agonists, receptors, protein kinases, intermediate molecules, transcription factors and tissue-specific gene expression compromise the functionality of skeletal muscle tissue, leading to muscle degeneration. Although considerable information has accumulated regarding the physiopathology of muscle diseases, the associated molecular mechanisms are still poorly understood. In this review, we will discuss the molecular basis of muscle atrophy, wasting and regeneration and the current gene and cell therapeutic approaches to attenuate atrophy and frailty associated with muscle diseases.