|Normal functioning of the mammalian Central Nervous System (CNS) depends on a high degree of interaction between its constitutive cell types. Although neurons represent the fundamental units of information processing in the CNS, a number of different glial cell types dynamically coordinate and modulate the final neuronal outputs. As a result, it is difficult to identify the relative contributions of individual cell types in the execution of complex CNS functions. Novel experimental tools for eliminating selected populations of glial cells are shedding light on the mechanisms underlying complex cell-to-cell interactions that influence the ultimate functionality of the brain and spinal cord. In particular, in vivo models of targeted cell death are making it possible to determine changes in natural phenomena in the absence of distinct subsets of glial cells, providing clues about the roles of those cells in neurophysiology. Distinct but complementary models of oligodendrocyte ablation, the topic of this review, are not only uncovering novel physiological roles for this subclass of glia in maintaining tissue homeostasis but also in the pathogenesis of demyelinating diseases. The goal of the current review is two-fold: to discuss various strategies developed to ablate populations of oligodendrocytes from awake, behaving animals and to identify the key contributions as well as the limitations of each model moving forward. Topics discussed include 1) whether primary oligodendrocyte death is sufficient to drive an autoimmune response that resembles multiple sclerosis, 2) the concept of a homeostatic mechanism for regulating the number of myelinating oligodendrocytes in the adult CNS, and 3) the copper-dependency of oligodendrocytes and its potential implications for demyelinating diseases. In the future, analyses of the data being generated both between and within these various animal models will be key to discovering novel roles for oligodendrocytes in both normal physiology and disease.