The use of psychostimulant drugs can modify brain function by inducing changes in the reward system, mainly due to alterations in dopaminergic and glutamatergic transmissions in the mesocorticolimbic pathway. However, the etiopathogenesis of addiction is a much more complex process. Previous data have suggested that microglia and other immune cells are involved in events associated with neuroplasticity and memory, which are phenomena that also occur in addiction. Nevertheless, how dependent is the development of addiction on the activity of these cells? Although the mechanisms are not known, some pathways may be involved. Recent data have shown psychoactive substances may act directly on immune cells, alter their functions and induce various inflammatory mediators that modulate synaptic activity. These could, in turn, be involved in the pathological alterations that occur in substance use disorder. Here, we extensively review the studies demonstrating how cocaine and amphetamines modulate microglial number, morphology, and function. We also describe the effect of these substances in the production of inflammatory mediators and a possible involvement of some molecular signaling pathways, such as the toll-like receptor 4. Although the literature in this field is scarce, this review compiles the knowledge on the neuroimmune axis that is involved in the pathogenesis of addiction, and suggests some pharmacological targets for the development of pharmacotherapy.