New therapies such as immune checkpoint blockers (ICB) have offered extended survival to patients affected by advanced melanoma. However, ICBs have demonstrated debilitating side effects on the joints, liver, lungs, skin, and gut. Several biomarkers have been identified for their role in predicting which patients better tolerate ICBs. Still, these biomarkers are limited by immunologic and genetic heterogeneity and the complexity of translation into clinical practice. Recent observational studies have suggested eosinophil counts, and serum levels of eosinophil cationic protein are significantly associated with prolonged survival in advanced-stage melanoma. It is likely that eosinophils thereby modulate treatment response through mechanisms yet to be explored. Here we review the functionality of eosinophils, their oncogenic role in melanoma and discuss how these mechanisms may influence patient response to ICBs and their implications in clinical practice.