Abstract
ORFans are open reading frames (ORFs) with no detectable sequence similarity to any other sequence in the databases. Each newly sequenced genome contains a significant number of ORFans. Therefore, ORFans entail interesting evolutionary puzzles. However, little can be learned about them using bioinformatics tools, and their study seems to have been underemphasized. Here we present some of the questions that the existence of so many ORFans have raised and review some of the studies aimed at understanding ORFans, their functions and their origins. These works have demonstrated that ORFans are an untapped source of research, requiring further computational and experimental studies.