Large-scale (~36,000 atoms) and long-time (30ns 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 longtime computational simulations offer insightful 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. 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). Contrary to current consensus, insights of novel imatinib resistance mechanisms are revealed and our findings suggest that drugs with different binding modes may be necessary to overcome the drug resistance due to T315I and other mutations. These insights are discussed in light of the recent relevant patent literature.