Shortly after the discovery of the eosinophil, increased numbers were identified in blood and tissues of numerous diseases, especially asthma. An association with anaphylaxis suggested a reparative eosinophil function, a dominant hypothesis for many years. However, the potent cytotoxic and cytostimulatory properties of granule proteins, particularly major basic protein (MBP1), argued that the eosinophil contributed to tissue damage; MBP1 tissue deposition was found in diseased tissues, often in the absence of intact eosinophils. Electron microscopy showed that eosinophils undergo cytolysis with release of intact granules into diseased tissues. The discovery of interleukin-5 (IL-5) as a key cytokine stimulating eosinophil production along with increased IL-5 levels in disease established its importance in driving eosinophil activity in disease. The hypothesis implicating the eosinophil as a mediator of disease activity has now been strengthened by demonstration that humanized monoclonal antibodies to IL-5 (mepolizumab and reslizumab) benefit patients with asthma by reducing exacerbations and by increasing pulmonary function. Notably, even in eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), a life-threatening disease, treatment with mepolizumab produced definite benefit. Although these findings strengthen the eosinophil hypothesis, perhaps the most compelling data comes from studies with antibody to the IL-5 receptor alpha chain that ablates eosinophils through an antibody-dependent cytotoxic reaction. Treatment with such an antibody benefits asthma, and, because it destroys eosinophils, support for the eosinophil hypothesis is strengthened further. Clinicians concerned with treatment of eosinophil-related disease currently have effective therapies to block IL-5, mepolizumab and reslizumab, thus inhibiting its actions on eosinophils. Presently, we do not know whether one may have a decisive advantage over the other generally or disease-specifically, and a current task for clinical investigation is to determine their effectiveness and relative benefits in eosinophil-related diseases.