Chronic inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are clinically and socioeconomically important diseases globally. Currently the mainstay of anti-inflammatory therapy in respiratory diseases is corticosteroids. Although corticosteroids have proven clinical efficacy in asthma, many asthmatic inflammatory conditions (e.g., infection, exacerbation, and severe asthma) are not responsive to corticosteroids. Moreover, despite an understanding that COPD progression is driven by inflammation, we currently do not have effective anti-inflammatory strategies to combat this disease. Hence, alternative anti-inflammatory strategies are required. p38 mitogen-activated protein kinase (MAPK) has emerged as an important signaling molecule driving airway inflammation, and pharmacological inhibitors against p38 MAPK may provide potential therapies for chronic respiratory disease. In this review, we discuss some of the recent in vitro and in vivo studies targeting p38 MAPK, but suggest that p38 MAPK inhibitors may prove less effective than originally considered because they may block anti-inflammatory molecules along with proinflammatory responses. We propose that an alternative strategy may be to target an anti-inflammatory molecule farther downstream of p38 MAPK, i.e., tristetraprolin (TTP). TTP is an mRNA-destabilizing, RNA-binding protein that enhances the decay of mRNAs, including those encoding proteins implicated in chronic respiratory diseases. We suggest that understanding the molecular mechanism of TTP expression and its temporal regulation will guide future development of novel anti-inflammatory pharmacotherapeutic approaches to combat respiratory disease.