The sequential accumulation of genetic alterations has been classically considered responsible for the origin and subsequent progression of colorectal cancer, although recent cumulative data provide strong evidence of the significance of epigenetic changes in the development of this multi-step malignancy. Among the epigenetic alterations, miRNAs deregulation has emerged as an exciting and promising field in cancer research. In a recent issue of the Journal of Pathology, Wang and colleagues identify miR-149 as being silenced by methylation in colorectal cancer. The authors also identified Sp1 as a target of miR-149. These intriguing observations have important biological prognostic and therapeutic implications.