 The microRNA, MIRNA-34 is a key regulator of tumor suppression that controls the expression of a plethora of target proteins involved in cell cycle, differentiation and apoptosis, and antagonizes processes necessary for basic cancer cell viability as well as cancer stemness, metastasis, and chemo-resistance. The MIR-34 role in modulating responsiveness to chemotherapy and phytonutrients mediated regulation of MIR-34 expression and activity in cancer cells are also discussed. A new therapeutic concept based on nanotechnology delivery of MIRNA mimics is proposed as an effective strategy against tumor heterogeneity, with selective RNA-based delivery systems being a promising platform for safe and effective targeting of the tumor. This article was authored by Gabriella Miso, Maria Teresa DeMartino, Giuseppe DeRosa, and others.