Drug discovery involves various steps and is a long process being even more demanding for complex diseases such as cancer. Tumors are ensembles of subpopulations with different mutations, require very specific and effective strategies. Conventional drug screening technologies may not be adequate and efficient anymore. Drug repositioning is a useful strategy to identify new uses for previously failed drugs. High throughput and deep sequencing technologies provide valuable support by yielding enormous amounts of "-omics" data and contribute to understanding the molecular mechanisms responsible for drug action. Computational methods coupled with systems biology represent a promising step to interpret pharmacogenomic data and establish strong connections with drug discovery. Genomic variations have been found to be linked with differential drug response among individuals. Large genome wide association studies are necessary to identify reliable connections between genomic variations and drug response since personalized medicine has been accepted as an important phenomenon in the drug discovery and development process post approval.