Elements of the cytoskeleton interact intimately and communicate bidirectionally with cellular membranes. Such interactions are critical for a host of cellular processes. Here we focus on the many types of interactions that exist between the cytoskeleton and the plasma membrane to illustrate why these cellular components can never truly be studied in isolation in vivo. We discuss how membrane-cytoskeleton interactions are mediated and modulated, and how many proteins involved in these interactions are disrupted in human disease. We then highlight key molecular and physical variables that must be considered in order to mechanistically dissect events associated with changes in plasma membrane morphology. These considerations are integrated into the context of cell migration, filopodia formation, and clathrin-mediated endocytosis to show how a holistic view of the plasma membrane-cytoskeleton interface can allow for the appropriate interpretation of experimental findings and provide novel mechanistic insight into these important cellular events.