Glucocorticoids (GCs) are the treatment of choice for chronic inflammatory diseases such as asthma. Despite proven effective anti-inflammatory and immunosuppressive effects, long-term and/or systemic use of GCs can potentially induce adverse effects. Strikingly, some recent experimental evidence suggests that GCs may even exacerbate some disease outcomes. In asthma, airway smooth muscle (ASM) cells are among the targets of GC therapy and have emerged as key contributors not only to bronchoconstriction, but also to airway inflammation and remodeling, as implied by experimental and clinical evidence. We here will review the beneficial effects of GCs on ASM cells, emphasizing the differential nature of GC effects on pro-inflammatory genes and on other features associated with asthma pathogenesis. We will also summarize evidence describing how GCs can potentially promote pro-inflammatory and remodeling features in asthma with a specific focus on ASM cells. Finally, some of the possible solutions to overcome these unanticipated effects of GCs will be discussed.Copyright © 2020. Published by Elsevier Inc.