PTB was initially discovered as a polypyrimidine tract-binding protein (hence the name), which corresponds to a specific RNA-binding protein associated with heterogeneous ribonucleoprotein particle (hnRNP I). The PTB family consists of three members in mammalian genomes, with PTBP1 (PTB) expressed in most cell types, PTBP2 (also known as nPTB or brPTB) exclusively found in the nervous system, and PTBP3 (also known as ROD1) predominately detected in immune cells. During neural development, PTB is down-regulated, which induces nPTB, and the expression of both PTB and nPTB becomes diminished when neurons mature. This programed switch, which largely takes place at the splicing level, is critical for the development of the nervous system, with PTB playing a central role in neuronal induction and nPTB guarding neuronal maturation. Remarkably, sequential knockdown of PTB and nPTB has been found to be necessary and sufficient to convert non-neuronal cells to the neuronal lineage. These findings, coupled with exquisite understanding of the molecular circuits regulated by these RNA-binding proteins, establish a critical foundation for their future applications in regenerative medicine.