Methods for identifying multigene biomarkers for predicting sensitivity or resistance to an anti-cancer drug of interest, or multigene cancer prognostic biomarkers are disclosed. The disclosed methods are based on the classification of the mammalian genome into 51 transcription clusters, i.e., non-overlapping, functionally relevant groups of genes whose intra-group transcript levels are highly correlated. Also disclosed are specific multigene biomarkers for predicting sensitivity or resistance to tivozanib, or rapamycin, and a specific multigene biomarker for determining breast cancer prognosis, all of which were identified using the methods disclosed herein.