Kinases are one of the most important targets in precision oncology, but the ideal kinase targets for most cancers have not been established. Determining the cellular consequences of turning off kinases has immense potential to transform our understanding of kinases and kinase inhibitors. We are deciphering how kinases regulate cancer cell function by using genome editing to turn off the activity of every kinase in the human genome. This approach will identify novel kinases for therapeutic targeting and will act as a surrogate for small-molecule inhibition to enable drug discovery. We will use this platform to interrogate how kinase activity regulates breast cancer cell growth, sensitivity to targeted therapies, and druggable gene expression. This will compress the interval between kinase hit and lead discovery from decades to years by identifying the optimal mechanisms to inhibit kinases, transforming drug development and the design of combination therapies.