Nature has always been a highly productive tool in the development of anticancer therapies. Renewed interest in the potential of this tool has recently been sparked by the realization that the marine ecosystem can be used for the discovery and development of new compounds with clinical potential in advanced resistant tumors. These compounds can be incorporated into combination approaches in a chronic therapy scenario. Our marine anticancer program is using the sea to develop new agents with activity in resistant solid tumors and to identify new cellular targets for therapeutic intervention. This review describes the integration of different pharmacogenomic tools in the development of Yondelis, Aplidin and Kahalalide F, three marine-derived compounds currently in Phase II or III development. Our results are reinforcing the targeted selectivity of these agents and opening the gates for customized therapies in cancer patients in the near future.