Systematic interrogation of multiple tumor genetic backgrounds with cancer drugs enables the identification of gene mutations that enhance or suppress the activity of those drugs. This identification has a great potential for improving drug efficacy and cancer therapy by providing insights into a drug mechanism-of-action, uncovering novel cancer vulnerabilities, and revealing strategies to tackle drug resistance mechanism. Despite the great advance in the development of targeted therapy, resistance to drugs is common. The advent of clustered regularly interspaced short palindromic repeats (CRISPR) gene editing technology and its adaptation to pooled library screens in mammalian cells greatly benefited this interrogation by enabling high quality chemogenetic screens to be carried directly in human cancer cell line. And with that, allowed us to identify tumor genetic backgrounds in which current drugs are effective; thus, expanding the use of targeted therapies. Other advantage of CRISPR system coupled with the ability to perform saturating genetic perturbation screens across many cell lines is the ability to identify synergistic and suppressor interactions explaining the genetic mechanisms of acquired or innate drug resistance.