The platelet cytoskeleton preserves the discoid shape of resting platelets and facilitates rapid shape changes in response to external stimuli at sites of vascular injury. In the resting state, specific cytoskeletal structures and molecules maintain the platelet’s unique architecture, anchor the actin cytoskeleton to the plasma membrane, and inhibit actin monomer polymerization. Upon activation, cytoplasmic signals interact with actin-regulatory proteins to drive actin filament growth, enabling the dynamic shape changes required for platelet function. This chapter explores the cellular mechanisms and proteins that regulate the morphology of resting and activated platelets, with an emphasis on the actin cytoskeleton, recent advances in mRNA and protein profiling, clinical observations, and insights from mouse models.