The mammalian central nervous system (CNS) is populated very early in development by tissue macrophages referred to as microglia. By adulthood, this CNS-resident population is found in all regions of the brain and spinal cord. Despite nearly a century of study, the in vivo function of microglia and the extent that they contribute to the onset, progression and recovery from neuroinflammatory disorders is still a subject of debate. Partly, the debate of whether activated microglia promote neuroprotection or neurodegeneration is fueled by the contrasting results derived from the different models used to assay microglial function. Here we discuss the strengths, weaknesses and utility of some of the most commonly used in vivo and in vitro models.