The overexpression of epidermal growth factor receptor (EGFR) is observed in several types of cancers including non-small cell lung cancer, head and neck, bladder, breast, and ovarian carcinomas. We are using computational techniques (molecular dynamics) to simulate the kinase domain of EGFR in complex with ATP competitive-inhibitors in an effort to determine origins of resistance to cancer causing and drug resistant mutations. Several analyses are used to evaluate the EGFR-ligand complexes including MM-GBSA post-processing to estimate the free energies of binding and molecular footprinting to examine per-residue interactions. The goal is to elucidate which energetic and structural features change for any given mutation in an effort to explain the experimentally observed differences in affinity.