Discovery of microRNAs (miRNAs) twenty years ago, has advocated a new era of “Molecular Genetics”. About 2000 miRNAs are present, that regulate one third of the genome. MiRNAs dysregulated expression may contribute to several diseases including tumor growth. Their presence in body fluids, reflecting levels alteration in various cancers, merit circulating miRNAs as the “next generation biomarkers” for early stages tumor diagnosis and/or prognosis. Herein, we performed a comprehensive literature search focusing on the origin, biosynthesis and role of miRNAs and summarized the foremost studies centering on miRs value as non-invasive biomarkers in different non-communicable diseases, including various cancer types. Moreover, during chemotherapy many miRNAs were linked to multidrug resistance, via modulating numerous biological processes and/or pathways that will be highlighted as well.