Platelet adhesion and activation are crucial for maintaining vascular integrity during hemostasis. Megakaryocytes, located in the bone marrow, are the direct precursors of blood platelets. It is estimated that a single megakaryocyte can produce between 1000 and 3000 platelets, and approximately 1011 platelets are produced daily in the human body (Harker LA, Finch CA, J Clin Invest 48:963–74, 1969). Defects in megakaryocyte maturation or platelet biogenesis can lead to thrombocytopenia, a condition characterized by low platelet counts, often accompanied by impaired platelet function. The cytoskeleton is crucial for platelet function. It maintains its discoid shape and reorganizes dynamically during activation. The platelet cytoskeleton consists of key proteins such as tubulin, actin, spectrin, and myosin, as well as various cytoskeleton-regulatory proteins. Similarly, cytoskeletal components are essential for the structural organization of megakaryocytes and the formation of their cytoplasmic protrusions, the proplatelets, which extend into bone marrow sinusoids. Inherited platelet function disorders are a rare group of diseases with mutations in genes encoding transcription factors and signaling or cytoskeletal proteins, among others, that can affect platelet number and function. In this chapter, we will focus on inherited platelet function disorders with mutations in cytoskeletal and cytoskeletal-regulatory proteins.