Drug discovery is strangled by extraordinary time consuming and costly processes associated with high failure rates. In the United States, less than 5% of drug candidates that enter drug testing will be approved by the Food and Drug Administration (FDA) and offered for clinic use. An emerging solution to overcome this bottleneck in new drug development is to repurpose presently available drugs, a practice also known as drug repurposing. In this chapter, a general overview of drug repurposing is reviewed, along with screening methods that have yield successful outcomes. Emphasis is given on utilizing RNA interference (RNAi) screening to identify druggable genes that can be targeted by drug repurposing.