The brain is a highly dynamic structure with the capacity for profound structural and functional change. Such neural plasticity has been well characterized within motor cortex and is believed to represent one of the neural mechanisms for acquiring and modifying motor behaviors. A number of behavioral and neural signals have been identified that modulate motor cortex plasticity throughout the lifespan in both the intact and damaged brain. Specific signals discussed in this review include: motor learning in the intact brain, motor relearning in the damaged brain, cortical stimulation, stage of development and genotype. Clinicians are encouraged to harness these signals in the development and implementation of treatment so as to maximally drive neural plasticity and functional improvements in speech, language and swallowing. Learning outcomes: Readers will be able to: (1) describe a set of behavioral and neural signals that modulate motor cortex plasticity in the intact and damaged brain; (2) describe the influence of stage of development on plasticity and functional outcomes; and (3) identify a known genotype that alters the capacity for motor learning and brain plasticity. (Contains 2 figures.)