The protocadherin family comprises clustered and nonclustered protocadherin genes. The nonclustered genes encode mainly d-protocadherins, which deviate markedly from classical cadherins. They can be subdivided phylogenetically into d0-protocadherins (protocadherin-20), d1-protocadherins (protocadherin-1, -7, -9, and -11X/Y), and d2-protocadherins (protocadherin-8, -10, -17, -18, and -19). d-Protocadherins share a similar gene structure and are expressed as multiple alternative splice forms differing mostly in their cytoplasmic domains (CDs). Some d-protocadherins reportedly show cell–cell adhesion properties. Individual d-protocadherins appear to be involved in specific signaling pathways, as they interact with proteins such as TAF1/Set, TAO2b, Nap1, and the Frizzled-7 receptor. The spatiotemporally restricted expression of d-protocadherins in various tissues and species and their functional analysis suggest that they play multiple, tightly regulated roles in vertebrate development. Furthermore, several d-protocadherins have been implicated in neurological disorders and in cancers, highlighting the importance of scrutinizing their properties and their dysregulation in various pathologies.