In this work, we identified the detrimental missense mutations (point mutations) in epidermal growth factor receptor (EGFR) and its binding efficiency with the inhibitors namely Erlotinib, Gefitinib, and Lapatinib. Out of 26 point mutations on EGFR, 12 point mutations were commonly less stable, deleterious, and damaged as shown by all the three servers, I-Mutant2.0, SIFT, and PolyPhen. Further, we modeled 12 mutants and superimposed with the native EGFR to get RMSD values. Docking studies showed that Erlotinib had lesser binding affinity against both native and all the 12 mutants. Gefitinib had maximum binding affinity only with two mutants, viz., R748P and L858R. Lapatinib had maximum binding affinity with both native and other 10 mutants. Based on our computational analysis, we recommend that the combined administration of Gefitinib and Lapatinib could give a better effect in combating the disease. © 2009 Humana Press.