Cerebellar development is shaped by the interplay of genetic and numerous environmental factors. Recent evidence suggests that cerebellar maturation is acutely sensitive to substances with abuse liability including alcohol, opioids, and nicotine. Assuming substance abuse disrupts cerebellar maturation, a central question is: what are the basic mechanisms underlying potential drug-induced developmental defects? Evidence reviewed herein suggests that the maturation of granule neurons and their progeny are intrinsically affected by several classes of substances with abuse liability. Although drug abuse is also likely to target directly other cerebellar neuron and glial types, such as Purkinje cells and Bergmann glia, findings in isolated granule neurons suggest that they are often the principle target for drug actions. Developmental events that are selectively disrupted by drug abuse in granule neurons and/or their neuroblast precursors include proliferation, migration, differentiation (including neurite elaboration and synapse formation), and programmed cell death. Moreover, different classes of drugs act through distinct molecular mechanisms thereby disrupting unique aspects of development. For example, drug-induced perturbations in: (i) neurotransmitter biogenesis; (ii) ligand and ion-gated receptor function and their coupling to intracellular effectors; (iii) neurotrophic factor biogenesis and signaling; and (iv) intercellular adhesion are all likely to have significant effects in shaping developmental outcome. In addition to identifying therapeutic strategies for drug abuse intervention, understanding the mechanisms by which drugs affect cellular maturation is likely to provide a better understanding of the neurochemical events that normally shape central nervous system development.