Greater manual dexterity and greater conceptual knowledge of tool use represent two main features that distinguish humans from other primates. Studies of human brain lesions suggest that the left hemisphere (at least in right-handed people) includes a system for processing manual skills that is specialized for tool use that interacts with another system involved more with conceptualizing, planning, and accessing knowledge associated with tool use. Growing evidence from recent neuroimaging studies supports this organization, and studies have begun to highlight specific brain regions and pathways that may be necessary for tool use. This review compares and summarizes results from 64 paradigms published over the past decade that have examined cortical regions associated with tool use skills and tool knowledge. A meta-analysis revealed cortical networks in both hemispheres, though with a clear left hemisphere bias, which may be organized to optimally represent action knowledge. Portions of this network appear to represent part of a system that is tightly linked with language systems, which is discussed together with the effects that handedness may have on the cortical organization for tool use.