Drug combination therapy provides a viable and promising way to overcome drug resistance in cancer treatment. Recent advances in automation and data analysis, increasing availabilities of compound libraries and better understanding of disease mechanisms have made high throughput screening a powerful tool to accelerate the development of drug combination therapy. Cumulative results, such as the AstraZeneca’s drug combination data set of the DREAM challenge and DrugComb, show that bioactive compounds, especially FDA-approved compounds and compounds being tested in clinical trials, are frequently used for combination screening because of their relatively clear biological activity and overall offer a high success rate of drug repurposing.