This chapter examines the powerful role of cultural mediation in human development. It reviews Lev Vygotsky's thinking on the topic of cultural mediation, including its hallmark achievements and also aspects that require further elaboration. The chapter presents arguments for a developmental account of cultural mediation and discusses its potential to demystify the power of signs to greatly enhance human psychological abilities. It summarizes that the contemporary research continues to struggle with the question about the unique role that signs might play in the operations of the human mind. Many scholars outside the cultural-historical framework make advances in answering this question but leave substantial gaps in their resulting conceptions. Finally, the chapter outlines the developmental continuum of emerging mediational means of growing complexity. The approach developed by Vygotsky can be used to advance a dialectial perspective on the link between the human mind and the world of culture.