The FW2.2 gene is associated with the major Quantitative Trait Locus (QTL) governing fruit size in tomato, and acts by negatively controlling cell division during fruit development. FW2.2 belongs to a multigene family named the CELL NUMBER REGULATOR (CNR) family. The CNR proteins harbour the uncharacterized PLAC8 motif made of two conserved cysteine-rich domains separated by a variable region that are predicted to be transmembrane segments, and indeed FW2.2 localizes to the plasma membrane. Although FW2.2 was cloned more than two decades ago, the molecular mechanisms of FW2.2 action remain unknown. Especially, how FW2.2 functions to regulate cell cycle and fruit growth, and thus fruit size, is yet not understood. We here review the current knowledge on PLAC8containing CNR/FWL proteins in plants, which are described to participate in plant organogenesis and the regulation of organ size, especially in fruits, and in Cadmium resistance, ion homeostasis and/or Ca2+ signalling. Within the plasma membrane, FW2.2 and some CNR/FWL are localized in microdomains, which is supported by recent data from interactomics studies. Hence FW2.2 and CNR/FWL could be involved in a transport function of signalling molecules across membranes, thus influencing organ growth via a cell-to-cell trafficking mechanism.