Glucocorticoids (GCs) are highly potent anti-inflammatory and immunosuppressive agents. They exert influence on many cell types of the immune system and impact a plethora of processes such as cytokine production, leukocyte differentiation, migration and adhesion, apoptosis induction, and changes in morphology. Those that are most relevant for the modulation of neuroinflammatory diseases, however, are still under debate. In this review, we will elaborate on how GCs impact inflammatory responses in general and revisit the ambivalent role that apoptosis plays in animal models of multiple sclerosis. Furthermore, we will discuss arguments that speak in favor or against an essential function of GC-induced apoptosis in neuroinflammation. We anticipate that a better knowledge of the mechanisms that GCs employ will eventually find its way into clinical practice for the future benefit of afflicted patients.