microRNAs (miRNAs) are master regulators of gene expression capable of defining and altering cell identity. Because of their potency, small size, simple mode of action (target recognition through a Watson-Crick type of base pairing) and the possibility to inhibit them in vivo, miRNAs are valuable therapeutic targets. Recently, we have used novel functional-genetic screening approaches and identified the miR-372, 373 and 520, as well as the miR-221&222 family as cancerous miRNAs. These miRNAs are oncogenes, as they are deregulated in specific types of cancers, target tumor suppressors and their inhibition reverts cancerous phenotypes. However, at present almost nothing is known about the mechanisms governing the expression and function of these, as well as many other, oncogenic miRNAs. Here, I propose experiments to identify and characterize factors affecting the activity of oncogenic miRNAs using an array of molecular and genetic tools. Our preliminary results indicate the existence of novel regulators and mechanisms of miRNA activity. We therefore believe that the information collected here not only will lead to a better understanding of miRNA functions, but will also identify novel modes of manipulating miRNA activity in human disease.