Corticosteroid-resistant asthmatics, although comprising only a portion of the asthma population, account for most of the morbidity, mortality and economic burden associated with asthma. Moreover, corticosteroids are not effective inhibitors of airway remodeling changes, and their long-term use is associated with debilitating systemic side effects. Therefore, potent and safe novel therapeutic alternatives, targeting basic pathophysiological mechanisms responsible for the severe asthmatic phenotype are urgently needed. Mitogen-activated protein kinases (MAPKs) are ubiquitously expressed signaling enzymes that are involved in almost all aspects of the asthmatic inflammatory network; as such, they represent an emerging target for the treatment of asthma. This paper provides a rationale for targeting MAPKs in the treatment of asthma by reviewing the in vitro evidence of its relevance to asthma pathogenesis. This is followed by discussing the results of MAPK inhibition in pre-clinical models of asthma. Finally, the potential safety concerns regarding MAPK inhibition in human disease, as well as the future prospects for its clinical development are explored. In conclusion, this review underlines the promising results of MAPK inhibition in animal asthma models especially in restoring corticosteroid sensitivity, as well as recent clinical safety and efficacy evidence obtained from trials in similar disease areas such as COPD, and of course, the paucity of clinical evidence for targeting MAPKs in asthma. Based on this review, a more rigorous effort for clinical development of MAPK inhibitors in asthma is justified.