Asthma is a complex, heterogeneous disorder with increasing prevalence. It is now recognized that several asthma phenotypes exist, including type 2-high and type 2-low (or non-type 2) subsets. As current research strives to identify subgroups of asthmatics that share disease pathobiology to establish endotypes, efforts to clarify the underlying molecular mechanisms of disease are needed and essential. IL-22 is thought to be a mediator of asthma pathogenesis, but whether this cytokine has a pathologic or beneficial role in the lung during severe disease is still debated. Studies focused on the regulation of this cytokine by its receptors and other inflammatory mediators during allergic airway responses are necessary to clarify its role in disease. Here, we discuss the ambiguity surrounding the role of IL-22 in asthma and considerations for targeting IL-22 therapeutically.