For two decades Vogelstein’s model has been theparadigm for describing the sequence of molecular changes within protein-coding genes that would lead to overt colorectal cancer(CRC). This model is now too simplistic in the light of recent studies, which have shown that our genome is pervasively transcribed in RNAs other than m RNAs, denominated non-coding RNAs(nc RNAs). The discovery that mutations in genes encoding these RNAs [i.e., micro RNAs(mi RNAs), long non-coding RNAs, and circular RNAs] are causally involved in cancer phenotypes has profoundly modified our vision of tumour molecular genetics and pathobiology. By exploiting a wide range of different mechanisms, nc RNAs control fundamental cellular processes, such as proliferation, differentiation, migration, angiogenesis and apoptosis: these data have also confirmed their role as oncogenes or tumor suppressors in cancer development and progression. The existence of a sophisticated RNA-based regulatory system, which dictates the correct functioning of protein-coding networks, has relevant biological and biomedical consequences. Different mi RNAs involved in neoplastic and degenerative diseases exhibit potential predictive and prognostic properties. Furthermore, the key roles of nc RNAs make them very attractive targets for innovative therapeutic approaches. Several recent reports have shown that nc RNAs can be secreted by cells into the extracellular environment(i.e., blood and other body fluids): this suggests the existence of extracellular signalling mechanisms, which may be exploited by cells in physiology and pathology. In this review, we will summarize the most relevant issues on the involvement of cellular and extracellular nc RNAs in disease. We will then specifically describe their involvement in CRC pathobiology and their translational applications to CRC diagnosis, prognosis and therapy. For two decades Vogelstein’s model has been theparadigm for describing the sequence of molecular changes within protein-coding genes that would lead to overt colorectal cancer (CRC). This model is now too simplistic in the light of recent studies, which have shown that our genome The discovery that the mutations in genes encoding these RNAs [ie, micro RNAs (mi RNAs), long non-coding RNAs, and circular RNAs] are pervasively transcribed in RNAs other than m RNAs, nodulated non-coding RNAs causally involved in cancer phenotypes has profoundly modified our vision of tumor spectrum molecular genetics and pathobiology. By exploiting a wide range of different mechanisms, nc RNAs control fundamental cellular processes, such as proliferation, differentiation, migration, angiogenesis and apoptosis: these data have also involved their role as oncogenes or tumor suppressors in cancer development and progression. The existence of a sophisticated RNA-based regulatory system, which dictates the c orrect functioning of protein-coding networks, has relevant biological and biomedical consequences. Different miRNAs involved in neoplastic and degenerative diseases exhibit potential predictive and prognostic properties. Several recent reports have shown that nc RNAs can be secreted by cells into the extracellular environment (ie, blood and other body fluids): this suggests the existence of extracellular signaling mechanisms, which may be exploited by cells in physiology and pathology. In this review, we will summarize the most relevant issues on the involvement of cellular and extracellular nc RNAs in disease. We will then specifically describe their involvement in CRC pathobiology and their translational applications to CRC diagnosis, prognosis and therapy.