Single microRNA (miRNA) can regulate expression of several or multiple principal targets in a specific microenvironment. In different cellular contexts, the same miRNA may exhibit diverse functions, depending on the repertoire and stoichiometry of its direct mRNA targets. For instance, in breast cancer, microRNA-10b (miR-10b) promotes invasion and metastasis of tumor cells through post-transcriptional regulation of HOXD10. In contrast, in glioblastoma (GBM), the most common and malignant primary brain tumor, miR-10b promotes proliferation and prevents death of cancer cells by targeting cell cycle inhibitors and pro-apoptotic genes. Here, we discuss a unique role of miR-10b in cancer cell survival, in diverse tumor microenvironments.