Coaches and clinicians refer to “best practices” when recognizing instructional environments that facilitate skill acquisition. Increasing contextual interference during training might be considered an evidenced-based best practice for learning skills commonly encountered in sports. The present work reviews new behavioral evidence that reveals that exposure to interleaved practice, a relatively high contextual interference training environment, facilitates learning and broad forms of generalization. Recent neurophysiological data, highlighted in this chapter, reveal distinct neural recruitment patterns apparent during interleaved but not repetitive practice formats that involve the participation of neural regions previously reported as central to motor skill learning including dorsal premotor and supplementary motor cortices. More extensive recruitment of these critical motor planning neural sites during interleaved practice is associated with the establishment of a very robust memory for skill that is quickly stabilized and remains very resistant to forgetting. These novel data support the use of greater contextual interference during training, as one evidence-based method, that can be used by sport coaches and instructors to induce sufficient “challenge” to the learner necessary to instigate critical neuro-plastic changes to support successful skill acquisition.