Non-coding RNAs (ncRNAs) play critical roles in all physiological processes. Many ncRNAs have also been implicated in a variety of pathological disorders, including cancer. This review provides an overview of the roles of small ncRNAs in infectious diseases and genetic disorders, including diseases of the CNS and various cancers. There is a focus on the consequences of microRNA (miRNA) de-regulation in human diseases, and recent progress in understanding other disease-related classes of ncRNAs, such as small nucleolar RNAs (snoRNAs), is presented. Finally, this review provides a brief perspective on new and powerful diagnostic strategies for human diseases that are based on ncRNA analysis, and presents novel potential approaches using ncRNAs as tools or targets for the treatment of such diseases.