Within many fungal syncytia, nuclei behave independently despite sharing a common cytoplasm. Creation of independent nuclear zones of control in one cell is paradoxical considering random protein synthesis sites, predicted rapid diffusion rates, and well-mixed cytosol. In studying the surprising fungal nuclear autonomy, new principles of cellular organization are emerging. We discuss the current understanding of nuclear autonomy, focusing on asynchronous cell cycle progression where most work has been directed. Mechanisms underlying nuclear autonomy are diverse including mRNA localization, ploidy variability, and nuclear spacing control. With the challenges fungal syncytia face due to cytoplasmic size and shape, they serve as powerful models for uncovering new subcellular organization modes, variability sources among isogenic uninucleate cells, and the evolution of multicellularity.