The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase commonly upregulated in various cancers, including non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. Various mechanisms, such as mutations and truncations in the extracellular domain and kinase domain, lead to overactivation of downstream pro-oncogenic signaling pathways, including the RAS-RAF-MEK-ERK MAPK and AKT-PI3K-mTOR pathways. These pathways activate numerous biological processes that promote cancer cell proliferation and progression through the cell cycle. This review covers the molecular mechanisms regulating EGFR signal transduction, including its structure, mutations, ligand binding, dimerization, and signaling pathways leading to G1 cell cycle progression. It focuses on the induction of CYCLIN D expression, CDK4/6 activation, and the repression of cyclin-dependent kinase inhibitor proteins (CDKIs) by EGFR signaling pathways. The review also discusses the successes and challenges of EGFR-targeted therapies and their potential use in combination with CDK4/6 inhibitors.The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase commonly upregulated in various cancers, including non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. Various mechanisms, such as mutations and truncations in the extracellular domain and kinase domain, lead to overactivation of downstream pro-oncogenic signaling pathways, including the RAS-RAF-MEK-ERK MAPK and AKT-PI3K-mTOR pathways. These pathways activate numerous biological processes that promote cancer cell proliferation and progression through the cell cycle. This review covers the molecular mechanisms regulating EGFR signal transduction, including its structure, mutations, ligand binding, dimerization, and signaling pathways leading to G1 cell cycle progression. It focuses on the induction of CYCLIN D expression, CDK4/6 activation, and the repression of cyclin-dependent kinase inhibitor proteins (CDKIs) by EGFR signaling pathways. The review also discusses the successes and challenges of EGFR-targeted therapies and their potential use in combination with CDK4/6 inhibitors.