Epidermal Growth Factor Receptor (EGFR) antagonists were one of the first anti-cancer treatments developed targeting a Receptor Tyrosine Kinase. However, the underlying mode of action of how EGFR antagonist application can explain its clinical efficacy in different types of cancers remains largely unresolved. Numerous findings have suggested that a substantial portion of the effects attributed to EGFR antagonist treatment might not be based on direct influence on the tumor itself. Instead it may be based on indirect effects, potentially mediated via the immune system. In this review the role of the EGFR for the functioning of the immune system is discussed, alongside how EGFR antagonist treatment could be impacting tumor growth by blocking macrophage and FoxP3-expressing regulatory CD4+ T cell function. Based on these findings, we consider implications for current treatment schemes and suggest novel approaches to improve the efficacy of EGFR antagonist treatment in the future. Finally, we propose potential ways to improve EGFR antagonists, in order to enhance their clinical efficacy whilst diminishing unwanted side effects.