 The microRNA, MIRNA-34A is a key regulator of tumor suppression that controls the expression of a plethora of target proteins involved in cell cycle, differentiation, apoptosis, and cancer cell viability, stemness, metastasis, and chemo-resistance. The molecular mechanisms of mere 34A mediated tumor suppression are discussed with emphasis on the main targets and principal regulators involved in its modulation. Additionally, the role of mere 34A in modulating responsiveness to chemotherapy and phytonutrients mediated regulation of its expression and activity in cancer cells is highlighted. A new therapeutic concept based on nanotechnology delivery of MIRNA mimics is discussed 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 Misso, Maria Teresa DeMartino, Giuseppe DeRosa, and others.