Neuroplasticity is the ability of the brain to reorganize itself during normal development and in response to illness. Recent advances in neuroimaging and direct cortical stimulation in human subjects have given neuroscientists a window into the timing and functional anatomy of brain networks underlying this dynamic process. This review will discuss the current knowledge about the mechanisms underlying neuroplasticity, with a particular emphasis on reorganization following CNS pathology. First, traditional mechanisms of neuroplasticity, most relevant to learning and memory, will be addressed, followed by a review of adaptive mechanisms in response to pathology, particularly the recruitment of perilesional cortical regions and unmasking of latent connections. Next, we discuss the utility and limitations of various investigative techniques, such as direct electrocortical stimulation (DES), functional magnetic resonance imaging (fMRI), corticocortical evoked potential (CCEP), and diffusion tensor imaging (DTI). Finally, the clinical utility of these results will be highlighted as well as possible future studies aimed at better understanding of the plastic potential of the brain with the ultimate goal of improving quality of life for patients with neurologic injury.