Mammalian cells employ an array of biological mechanisms to detect and respond to mechanical loading in their environment. One such mechanism is the formation of plasma membrane disruptions (PMD), which foster a molecular flux across cell membranes that promotes tissue adaptation. Repair of PMD through an orchestrated activity of molecular machinery is critical for cell survival, and the rate of PMD repair can affect downstream cellular signaling. PMD have been observed to influence the mechanical behavior of skin, alveolar, and gut epithelial cells, aortic endothelial cells, corneal keratocytes and epithelial cells, cardiac and skeletal muscle myocytes, neurons, and most recently, bone cells including osteoblasts, periodontal ligament cells, and osteocytes. PMD are therefore positioned to affect the physiological behavior of a wide range of vertebrate organ systems including skeletal and cardiac muscle, skin, eyes, the gastrointestinal tract, the vasculature, the respiratory system, and the skeleton. The purpose of this review is to describe the processes of PMD formation and repair across these mechanosensitive tissues, with a particular emphasis on comparing and contrasting repair mechanisms and downstream signaling to better understand the role of PMD in skeletal mechanobiology. The implications of PMD-related mechanisms for disease and potential therapeutic applications are also explored.