In this chapter we review evidence for two complementary theories of the neural organization of human tool use. First, it is likely that experience-dependent modifications to preexisting neural substrates devoted to hand control and common to other living primates are essential. These mechanisms are highly and acutely plastic, and this acute plasticity is essential for learning new sensorimotor control mappings between tools and the body, and for adaptively changing between them. Second, the evidence also suggests that more complex human tool use behavior relies on additional cortical substrates, some of which may be uniquely human. A core network of predominately left-lateralized and highly functionally fractionated brain areas including inferior parietal, middle frontal, and posterior middle temporal cortex appear to be essential. Inferior parietal and posterior middle temporal areas may have undergone disproportionate expansion throughout the course of human evolution, and the connective properties that link these areas with frontal cortex may be uniquely human.