The first discovery that interleukin-4 (IL-4) is crucial in the development of allergic airway inflammation originates from the early 1990s. Whereas initial studies in experimental animal models provided the community with the optimistic view that targeting IL-4 would be the ultimate solution for treating asthma, the translation of these findings to the clinic has not been evident and has not yet fulfilled the expectations. Many technical challenges have been encountered in the attempts to modulate IL-4 expression or activity and in transferring knowledge of preclinical studies to clinical trials. Moreover, biological redundancies between IL-4 and IL-13 have compelled a simultaneous blockade of both cytokines. A number of phase I/II studies are now providing us with clinical evidence that targeting IL-4/IL-13 may provide some clinical benefit. However, the initial view that asthma is a purely Th2-mediated disease had to be revised. Currently, different asthma phenotypes have been described, implying that blocking specifically Th2 cytokines, such as IL-4, IL-5, and IL-13, should be targeted to only a specific subset of patients. Taking this into consideration, IL-4 (together with IL-13) deserves attention as subject of further investigations to treat asthma. In this review, we will address the role of IL-4 in asthma, describe IL-4 signaling, and give an overview of preclinical and clinical studies targeting the IL-4 Receptor pathway.