Following injury to the central nervous system, secondary degeneration is mediated by Ca2+ imbalances and overproduction of reactive oxygen species from mitochondria, and is associated with myelin deficits and loss of function. Preventing intracellular Ca2+ influx at the acute phase of injury is a potential strategy for limiting these deficits and preserving function. The use of single ion channel inhibitors has had little success in attenuating morphological and functional deficits, potentially due to the many pathways by which calcium can traverse the cell membrane. Focus has shifted to the simultaneous administration of a combination of ion channel inhibitors: lomerizine, oxATP, and YM872. The combination has resulted in reductions in oxidative damage, as well as preservation of function and myelin ultrastructure, potentially due to the protection of oligodendrocytes and their progenitors. The use of multiple ion channel inhibitors is promising and suggests a reduction in total intracellular Ca2+ influx is necessary and sufficient for the protection of neurons and glia following neurotrauma. Optimization of treatment timing, inhibitor choice, and method of delivery will be required for translation of this strategy to the clinic.