Dysregulation of micro RNAs is crucially implicated in tumorigenesis. We detected downregulation of miR-100 in breast cancer cells, leading to an upregulation of the proliferation- and survival-promoting oncogene insulin-like growth factor (IGF) 2. Stable overexpression of miR-100 strongly reduced IGF2 expression and inhibited tumor growth. In invasive human breast tumors, miR-100 was reduced about fourfold as compared with benign patient samples, whereas IGF2 was strongly enhanced. MiR-100 has also been shown to suppress other proteins of the IGF/mammalian target of rapamycin (mTOR) signaling cascade in different human tumors. Our results reveal miR-100 as a context-dependent master regulator of the IGF/mTOR pathway and a potential target for therapeutic approaches.