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Membrane microdomains/nanodomains are sub-compartments of the plasma membrane enriched in sphingolipids and characterized by their unique protein composition. They play important roles in regulating plant development and plant-microbe interactions including mutualistic symbiotic interactions. Several protein families are associated with the microdomain fraction of biological membranes such as flotillins, prohibitins, and remorins. More recently, GmFWL1, a FWL/CNR protein exclusively expressed in the soybean nodule, was functionally characterized as a new microdomain-associated protein. Interestingly, GmFWL1 is homologous to the tomato FW2-2 protein, a major regulator of tomato fruit development. In this review, we summarize the knowledge gained about the biological, cellular, and physiological functions of members of the FWL/CNR family across various plant species. The role of the FWL/CNR proteins is also discussed within the scope of their evolution and transcriptional regulation.