Although myxomycetes (plasmodial slime molds) are unicellular organisms, they are distinguished by a unique ecological feature in that they grow to huge sizes while remaining a single cell. Even more astonishingly, they can accurately distinguish self from non-self. Even within the same species, plasmodia from different localities may spend several hours assessing one another and, if they are incompatible for fusion, move apart without fusing. They can also distinguish compatible from incompatible individuals without direct contact, apparently using signaling substances in the secreted slime sheath. Understanding allorecognition (self–non-self recognition) in myxomycetes may help clarify the evolutionary origins of multicellularity and what constitutes “self” in an organism.