Abstract: A method of identification of drug targets and drug resistance mechanisms in human cells of a drug comprising the steps of: generating at least one drug-resistant sample and at least one drug-sensitive sample; analyzing substantial portions of the genome and/or transcriptome of the least one drug-resistant sample and drug-sensitive sample to obtain sequencing data; detecting substantially all alterations in the at least drug-resistant sample; deriving a resistance signature; and performing analysis of the drug resistance signature of at least one recurrently altered gene using bioinformatic tools and cellular biology methods to determine if alteration of the at least one gene of the drug resistance signature is sufficient to confer at least partial resistance to cells or tissues against the drug.