The developing nervous system has been long recognized as a primary target for a variety of toxicants. To date, most efforts to understand the impact of neurotoxic agents on the brain have focused primarily on neurons and to a lesser degree astroglia as cellular targets. The role of oligodendroglia, the myelin-forming cells in the central nervous system (CNS), in developmental neurotoxicity has been emphasized only in recent years. Oligodendrocytes originate from migratory, mitotic progenitors that mature progressively into postmitotic myelinating cells. During differentiation, oligodendroglial lineage cells pass through a series of distinct phenotypic stages that are characterized by different proliferative capacities and migratory abilities, as well as dramatic changes in morphology with sequential expression of unique developmental markers. In recent years, it has become appreciated that oligodendrocyte lineage cells have important functions other than those related to myelin formation and maintenance, including participation in neuronal survival and development, as well as neurotransmission and synaptic function. Substantial knowledge has accumulated on the control of oligodendroglial survival, migration, proliferation, and differentiation, as well as the cellular and molecular events involved in oligodendroglial development and myelin formation. Recently, studies have been initiated to address the role of oligodendrocyte lineage cells in neurotoxic processes. This article examines recent progress in oligodendroglial biology, focuses attention on the characteristic features of the oligodendrocyte developmental lineage as a model system for neurotoxicological studies, and explores the role of oligodendrocyte lineage cells in developmental neurotoxicity. The potential role of oligodendroglia in environmental lead neurotoxicity is presented to exemplify this thesis.