Disease phenotypes are often regulated by interwoven genetic networks. For example, tumor genomes exhibit an extensive variety of genetic and epigenetic changes involved in tumor initiation, metastasis and ultimately, resistance to therapy. Combination therapy to target multiple pathways, as opposed to only single ones, can enhance treatment efficacy. Discovering effective combination therapies for human diseases is challenging with existing methods, due to the cost, effort, and labor required to construct and analyze each combination. There is a need for technological advances to accelerate the identification of effective combinatorial therapies. CRISPR has emerged as a new tool to systemically interrogate cancer genomes and set up the potential for personalized medicine. Personalized medicine is based upon the concept that individual differences can be identified and used to the patient’s advantage for therapy.