Large-scale (∼36,000 atoms) long-time (30 ns each) molecular dynamics (MD) simulations on the complex of imatinib and 16 common mutants of the ABL tyrosine kinase domain have been performed to study the imatinib resistance mechanisms at the atomic level. MD simulations show that long time computational simulations could offer insight information that static models, simple homology modeling methods, or short-time simulations cannot provide for the BCR-ABL imatinib resistance problem. Three possible types of mutational effects from those mutants are found: the direct effect on the contact interaction with imatinib (e.g. some P-loop mutations), the effect on the conformation of a remote region contacting with imatinib (e.g. T315I), and the effect on interaction between two regions within the BCR-ABL domain (e.g. H396P). Insights of possible imatinib resistance mechanisms, not consistent with current consensus, are revealed from various analyses and our findings suggest that drugs with different binding modes may be necessary to overcome the drug resistance due to T315I and other mutations. The relevant patents are discussed.