The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly upregulated in various cancers, including non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. EGFR activity is regulated by various mechanisms, including mutations and truncations in its extracellular and kinase domains, such as EGFRvIII truncations, L858R and T790M mutations, and exon 19 truncation. These aberrations over-activate downstream pro-oncogenic signaling pathways, including the RAS-RAF-MEK-ERK MAPK and AKT-PI3K-mTOR pathways, which promote cancer cell proliferation by activating biological outputs that support cell cycle progression. This review discusses the molecular mechanisms that regulate EGFR signal transduction, including its structure, mutations, ligand binding, and dimerization, as well as the signaling pathways that lead 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 (CDKi) 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 EGFR is a member of the ErbB family, which includes EGFR/ERBB1/HER1, NEU/ERBB2/HER2, ERBB3/HER3, and ERBB4/HER4. These family members can form homo- and heterodimers, leading to a total of 28 different combinations. The EGFR is synthesized as a 1210 residue precursor that is cleaved at the N-terminal to result in the mature 1186 residue transmembrane EGFR. The EGFR consists of an extracellular ligand binding and dimerization arm, a hydrophobic transmembrane domain, and an intracellular tyrosine kinase and C-terminal tail domain. EGFR mutations occur at mutational “hotspots” in the extracellular region, the kinase domain, and the C-terminal tail. Certain types of cancers appear to favor certain locations for their mutations. For example, most glioblastomas appear to harbour aberrations to the ectodomain, whereas non-small cell lung cancers (NSCLCs) almost exclusively harbour kinase domain mutations. EGFR mutations and truncations can impart the EGFR with ligand-independent signaling, which lead to the upregulation of various pro-oncogenic processes, including chronic cell cycle proliferation. The EGFR is activated by ligand binding, leading to receptor dimerization, transphosphorylation of the C-terminal tail, and propagation of the signal through various intricate signaling pathways to induce the expression of new genes. The EGFR's link to cancer was firstThe epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly upregulated in various cancers, including non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. EGFR activity is regulated by various mechanisms, including mutations and truncations in its extracellular and kinase domains, such as EGFRvIII truncations, L858R and T790M mutations, and exon 19 truncation. These aberrations over-activate downstream pro-oncogenic signaling pathways, including the RAS-RAF-MEK-ERK MAPK and AKT-PI3K-mTOR pathways, which promote cancer cell proliferation by activating biological outputs that support cell cycle progression. This review discusses the molecular mechanisms that regulate EGFR signal transduction, including its structure, mutations, ligand binding, and dimerization, as well as the signaling pathways that lead 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 (CDKi) 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 EGFR is a member of the ErbB family, which includes EGFR/ERBB1/HER1, NEU/ERBB2/HER2, ERBB3/HER3, and ERBB4/HER4. These family members can form homo- and heterodimers, leading to a total of 28 different combinations. The EGFR is synthesized as a 1210 residue precursor that is cleaved at the N-terminal to result in the mature 1186 residue transmembrane EGFR. The EGFR consists of an extracellular ligand binding and dimerization arm, a hydrophobic transmembrane domain, and an intracellular tyrosine kinase and C-terminal tail domain. EGFR mutations occur at mutational “hotspots” in the extracellular region, the kinase domain, and the C-terminal tail. Certain types of cancers appear to favor certain locations for their mutations. For example, most glioblastomas appear to harbour aberrations to the ectodomain, whereas non-small cell lung cancers (NSCLCs) almost exclusively harbour kinase domain mutations. EGFR mutations and truncations can impart the EGFR with ligand-independent signaling, which lead to the upregulation of various pro-oncogenic processes, including chronic cell cycle proliferation. The EGFR is activated by ligand binding, leading to receptor dimerization, transphosphorylation of the C-terminal tail, and propagation of the signal through various intricate signaling pathways to induce the expression of new genes. The EGFR's link to cancer was first