The Wiskott-Aldrich syndrome protein (WASp) is a key regulator of actin polymerization in hematopoietic cells. The dynamic nature of cytoskeletal changes during a variety of cellular processes demands complex mechanisms for coordinated integration of input signals, precise localization within the cell, and regulated activation of the Arp2/3 complex. Mutations in the Wiskott-Aldrich syndrome gene either inhibit or dysregulate normal WASp function, resulting in clinical diseases with complex and disparate phenotypes. This review highlights recent advances that have enhanced our understanding of the mechanisms by which these molecular defects cause hematologic and immunologic disease.