 The microRNA, mRNA-34 is a key regulator of tumor suppression that controls the expression of target proteins involved in cell cycle, differentiation, apoptosis, cancer cell viability, stymness, metastasis, and chemoresistance. Its molecular mechanisms of tumor suppression are discussed, along with its role in modulating responsiveness to chemotherapy and phytonutrients mediated regulation of mere 34 expression and activity in cancer cells. A new therapeutic concept based on nanotechnology delivery of mRNA mimics is also discussed as an effective strategy against tumor heterogeneity. This article was authored by Gabriela Misso, Maria Teresa de Martino, Giuseppe de Rosa, and others.