Choosing the right cell-based screen from the plethora of options available can quickly become a complicated decision process. Here, we review two of the major options: cell panel and functional genomic screening. Cell panel screening provides drug response data across panels of genomically diverse cell lines from different tissue types. These screens can provide evidence of drug resistance and sensitivity; aid selection of efficacious drugs for treatment of a specific disease; stratify patients for clinical trials; repurpose drugs with clinically acceptable profiles and provide data to inform mechanism of action (MoA) studies. Functional Genomic Screening (FGS), where RNAi or CRISPR is used to modify gene expression, can also address many similar questions to cell panel screens, but from a genetic point of view. In addition, FGS can be used to find and validate novel drug targets, identify the genetic basis of drug resistance or sensitivity, and identify genetic dependencies (often referred to as synthetic lethality).