Epidermal growth factor receptor (EGFR) is frequently mutated in non-small cell lung cancer (NSCLC) where it has been successfully targeted with tyrosine kinase inhibitors, but these are eventually overcome by drug resistance. Overcoming this therapeutic challenge has been hindered by the poor understanding of how wild type (WT)-EGFR elicits ligand-independent signals essential for cell homeostasis, which are then hijacked by cancer mutations. Ligand-independent signaling cannot be explained by the autoinhibited ligand-free EGFR dimer and oligomer structures so far available. Here we show that EGFR achieves ligand-independent phosphorylation by assembling dimer conformers into obligate ligand-free hetero-conformational oligomers. We reveal the structure of these ligand-free oligomers and their mechanisms of assembly. We also show how these mechanisms are exploited by drug-resistant T766M and Ex20ins EGFR mutants, revealing oncogenic functions for hitherto orphan transmembrane and kinase interfaces, and for the ectodomain tethered conformation of EGFR. Our findings provide a framework for future drug discovery directed at tackling EGFR mutations in cancer by disabling oligomer-assembling interactions.