Phosphotyrosine-binding (PTB) domains are ubiquitous protein domains found on scaffold proteins. They play key roles as docking sites in many cellular signaling pathways. They are versatile domains due to wide range of ligand recognition and sequence flexibility. PTB domains are evolutionarily derived from the PH domain, but with additional structural modifications to the N-terminus resulting in the formation of secondary binding pocket. This allows the PTB domain to have two separate functional binding pockets, PTB cores, resulting in an additional layer of signaling control. Both PTB cores can be further reduced to minimal core motifs, PTB-mCore, the most reduced form of the PTB domain that retains functionality. A PTB-mCore contains one α helix and one β sheet with two β strands, as the basic structural motifs in ligand binding. PTB domains can be structurally classified as typical and atypical ones. The atypical PTB cores are structurally similar to the typical PTB-mCore. Discovery of additional atypical PTB domain-containing proteins may greatly increase the pool of possible ligand partners in cellular conditions. Both PTB cores are able to bind similarly to NPXY motifs. This dual core theory explains the mismatch in the multiple redundant NPXY motifs seen in the cytoplasmic tails of many membrane receptors and receptor tyrosine kinases (RTKs) that bind to only a single PTB domain. Furthermore, in the interaction of CCM2 and CCM1, it was seen that a point mutation of one CCM2 PTB core without any structural perturbation of the neighboring core is sufficient for disease phenotype suggesting that both PTB cores have an independent role in CCM2 function. We summarize the recent advancements in the last five years of the PTB domain which will further increase understanding of these versatile domains and the numerous signaling pathways they play a key role in.