In the recent past, our knowledge on small non-protein-coding RNAs (ncRNAs) has exponentially grown. Different approaches to identify novel ncRNAs that include computational and experimental RNomics have led to a plethora of novel ncRNAs. A picture emerges, in which ncRNAs have a variety of roles during regulation of gene expression. Thereby, many of these ncRNAs appear to function in guiding specific protein complexes to target nucleic acids. The concept of RNA guiding seems to be a widespread and very effective regulatory mechanism. In addition to guide RNAs, numerous RNAs were identified by RNomics screens, lacking known sequence and structure motifs; hence no function could be assigned to them as yet. Future challenges in the field of RNomics will include elucidation of their biological roles in the cell.