The present invention provides methods for conducting screens using nucleic acid elements (e.g., interfering RNAs) to confidently identify hit genetic elements. The present invention further comprises constructing vectors that contain two or more nucleic acid elements to knock down all pairwise combinations of the hit genetic elements identified from the screen. Following quantitation of the single and double-knockdown phenotypes, genetic interactions between all gene pairs can be calculated. Genes can then be clustered according to the similarity of the pattern of their interactions with all of the other genes to obtain a genetic interaction map, which can advantageously be used to predict functional associations between genes and identify drug targets for therapy such as combination cancer therapy.