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Short or small interfering RNAs (siRNAs) and microRNA (miRNAs) are molecules similar in size and function able to inhibit gene expression based on their complementarity with mRNA sequences, inducing the degradation of the transcript or the inhibition of their translation.siRNAs bind specifically to a single gene location by sequence complementarity and regulate gene expression by specifically targeting transcription units via posttranscriptional gene silencing. miRNAs can regulate the expression of different gene targets through their imperfect base pairing.This process - known as RNA interference (RNAi) - modulates transcription in order to maintain a correct physiological environment, playing a role in almost the totality of the cellular pathways.siRNAs have been evolutionary evolved for the protection of genome integrity in response to exogenous and invasive nucleic acids such as transgenes or transposons. Artificial siRNAs are widely used in molecular biology for transient silencing of genes of interest. This strategy allows to inhibit the expression of any target protein of known sequence and is currently used for the treatment of different human diseases including cancer.Modifications and rearrangements in gene regions encoding for miRNAs have been found in cancer cells, and specific miRNA expression profiles characterize the developmental lineage and the differentiation state of the tumor. miRNAs with different expression patterns in tumors have been reported as oncogenes (oncomirs) or tumor-suppressors (anti-oncomirs). RNA modulation has become important in cancer research not only for development of early and easy diagnosis tools but also as a promising novel therapeutic approach.Despite the emerging discoveries supporting the role of miRNAs in carcinogenesis and their and siRNAs possible use in therapy, a series of concerns regarding their development, delivery and side effects have arisen.In this review we report the biology of miRNAs and siRNAs in relation to cancer summarizing the recent methods described to use them as novel therapeutic drugs and methods to specifically deliver them to cancer cells and overcome the limitations in the use of these molecules., (© 2021. The Author(s).)