The increasingly diverse student population within classrooms potentially stretches the competencies of every teacher. Differentiated instruction has been offered to help teachers accommodate diverse learners, but most instructional strategies are typically directed at compensating for - not remediating - cognitive and academic skill deficits. This differentiated instruction approach is contrasted with the extant learning science and educational neuroscience literature, which suggests early intervention and remediation of skill deficits is the preferred evidence-based practice. To overcome these competing and apparently contradictory positions, we argue children should be provided with systematic brain-based differentiated instruction in inclusive classrooms to prevent skill deficits, with compensatory accommodations provided only as necessary to help children access the general education curriculum. For those who continue to struggle, we argue remedial efforts should occur outside of, and in addition to, inclusive general education instruction, given the empirical evidence supporting both practices. Implications for training and system-level reform will be addressed.