Abstract Motivation Genetic alterations lead to tumor progression and cell survival but also uncover cancer-specific vulnerabilities on gene dependencies that can be therapeutically exploited. Results vulcanSpot is a novel computational approach implemented to expand the therapeutic options in cancer beyond known-driver genes unlocking alternative ways to target undruggable genes. The method integrates genome-wide information provided by massive screening experiments to detect genetic vulnerabilities associated to tumors. Then, vulcanSpot prioritizes drugs to target cancer-specific gene dependencies using a weighted scoring system based on well known drug-gene relationships and drug repositioning strategies. Availability and implementation http://www.vulcanspot.org. Supplementary information Supplementary data are available at Bioinformatics online.