Abstract Objective To review and highlight the unappreciated roles of eosinophils suggested by recent studies. Data Sources The literature, unpublished observations, and insights by the authors. Study Selections Basic studies of mouse models and patient-based clinical studies of disease. Results Eosinophils are often thought of as destructive end-stage effector cells primarily linked to parasite host defense and dysregulated immune responses associated with allergic diseases, such as asthma. However, recent studies (ie, research focused on mechanisms of action and translational studies examining disease/inflammatory pathways) are suggesting far more complex roles for eosinophils. The goal of this review is 3-fold. (1) The authors examine the dynamic history of eosinophils and how physicians over time used this information to formulate defining hypotheses. Particular emphasis is placed on recent studies challenging the parochial view of host defense in favor of roles maintaining homeostasis through immune modulation and tissue remodeling/repair. (2) They discuss diagnostic approaches to assess eosinophils in clinical settings as a means of disease identification and subsequently as a measurement of disease severity. (3) They examine how contemporary views of eosinophils and their perceived roles in diseases have led to specific therapeutic strategies. The emphasis is to review the successes and failures of these strategies as the basis of formulating future clinical studies targeting eosinophils as potential therapies of disease. Conclusion Despite the complexities of eosinophil-mediated activities and the less than overwhelming success of initial attempts targeting these cells, eosinophils remain a potentially important focal target of disease diagnosis and subsequent treatment strategies.