Deep sequencing approaches have revealed multiple types of small RNAs with known and unknown functions. In this review we focus on a recently identified group of small RNAs that are derived from transfer RNAs (tRNAs), tRNA fragments (tRFs). We review the mechanism of their processing and their functions in mammalian cells, and highlight points of possible cross-talk between tRFs and the canonical small RNA pathway characterized by small interfering RNAs (siRNAs), microRNAs (miRNAs), and Piwi-interacting RNAs (piRNAs). We also propose a nomenclature that is based on their processing characteristics.