The loss of muscle mass and strength with aging, also referred to as sarcopenia of aging, is a highly prevalent condition among older adults and predicts several adverse outcomes, including disability, institutionalization and mortality. Although the exact mechanisms underlying sarcopenia are far to be unveiled, accumulating preclinical evidence suggests that an age-related acceleration of myocytes loss via apoptosis might represent a key mechanism driving the onset and progression of muscle loss. Furthermore, increased levels of apoptosis have also been reported in old rats undergoing acute muscle atrophy subsequent to muscle unloading, a condition that mimics the muscle loss observed during prolonged bed rest. Notably, preliminary evidence seems to confirm a causative role for apoptosis in age-related muscle loss in human subjects. Several signaling pathways of skeletal muscle apoptosis are currently under intense investigation, with a particular focus on the role played by mitochondria. Here, we will review the most recent evidence regarding various pathways of muscle apoptosis and their modulation by several interventions (caloric restriction, physical exercise, muscle unloading).