Simple SummaryExtracellular vesicles (EVs), consisting of microvesicles and exosomes, serve as messengers for intercellular communication by transporting proteins and nucleic acids. In solid cancers of epithelial origin, Epidermal Growth Factor Receptor (EGFR) plays a pivotal role as a driver. In vitro studies conducted on EGFR-dependent solid tumours revealed the significant correlation between EGFR and EVs production, leading to the dissemination of EGFR itself and related molecules along with inducing cell proliferation, modifying the tumour microenvironment, facilitating metastases, and conferring resistance to treatments. Recently, liquid biopsy approaches started to exploit the interplay of EGFR and EVs in delivering proteins, RNAs, and DNAs via blood/plasma of EGFR-dependent tumour patients to evaluate their possible roles and applications as candidate biomarkers in diagnosing and monitoring tumour progression and therapy efficacy.AbstractExtracellular vesicles (EVs) are of great interest to study the cellular mechanisms of cancer development and to diagnose and monitor cancer progression. EVs are a highly heterogeneous population of cell derived particles, which include microvesicles (MVs) and exosomes (EXOs). EVs deliver intercellular messages transferring proteins, lipids, nucleic acids, and metabolites with implications for tumour progression, invasiveness, and metastasis. Epidermal Growth Factor Receptor (EGFR) is a major driver of cancer. Tumour cells with activated EGFR could produce EVs disseminating EGFR itself or its ligands. This review provides an overview of EVs (mainly EXOs and MVs) and their cargo, with a subsequent focus on their production and effects related to EGFR activation. In particular, in vitro studies performed in EGFR-dependent solid tumours and/or cell cultures will be explored, thus shedding light on the interplay between EGFR and EVs production in promoting cancer progression, metastases, and resistance to therapies. Finally, an overview of liquid biopsy approaches involving EGFR and EVs in the blood/plasma of EGFR-dependent tumour patients will also be discussed to evaluate their possible application as candidate biomarkers.