Current issues related to motor sequence learning in humans

•Behavioral determinants and neural correlates of motor sequence learning.•Advances in methodological approaches and neuroimaging data analyses.•Motor sequence acquisition and consolidation in healthy and clinical populations.•Current challenges in the development of non-invasive clinical interventions. The learning of sequential motor behaviors involves the integration of separate movements into a unified and coordinated sequence of actions through practice. Neuroimaging studies in humans strongly suggest that this form of procedural memory relies on the progressive reorganization of motor-related neural networks over the course of learning. This experience-driven reorganization of internal task representations is also subserved by consolidation processes that require time, and sometimes sleep, to become effective, hence constituting the mechanism by which long-term memory of the skill is achieved. In this review, we present the current understanding of the behavioral determinants, brain functional plasticity and neurophysiological processes related to the formation and long-term retention of motor sequence knowledge. Insights from clinical research and their practical implications, with the development of non-invasive and patient-oriented interventions, are also discussed.