A computational approach for identifying active miRNAs and miRNA-mediated regulatory mechanisms. Applying ActMiR to four cancer datasets in The Cancer Genome Atlas (TCGA), we showed that (1) miRNA activity was tumor subtype specific; (2) genes correlated with inferred miRNA activities were more likely to enrich for miRNA binding motifs; (3) expression levels of these genes and inferred miRNA activities were more likely to be negatively correlated. In summary, inferred activity of key miRNA provided a functional link to its mediated regulatory network, and can be used to robustly predict patient's survival.