Phospholipids in cell membranes undergo hop diffusion, moving between compartments of 230-nm diameter, confined for 11 ms before hopping to adjacent compartments. This compartmentalization reduces lipid diffusion rates by a factor of 5–100 compared to artificial bilayers. The cell membrane is not compartmentalized by cholesterol-enriched rafts, extracellular matrix, or extracellular domains of membrane proteins, but rather by the actin-based membrane skeleton. Transmembrane proteins anchored to the actin-based membrane skeleton act as rows of pickets, temporarily confining phospholipids through steric hindrance and circumferential slowing. This model explains the observed reduction in lipid diffusion and supports the idea that the cell membrane is compartmentalized with regard to lateral diffusion of phospholipids. DOPE, an unsaturated phospholipid, diffuses rapidly within 230-nm compartments but is slowed when moving between compartments. The NRK cell membrane is doubly compartmentalized, with phospholipids confined in 230-nm compartments and also in larger 750-nm compartments. This double compartmentalization is consistent with the involvement of the actin-based membrane skeleton in lipid diffusion. The results suggest that the actin-based membrane skeleton plays a critical role in regulating lipid diffusion and in the localization of intracellular signals. The study provides evidence for the anchored-protein picket model, in which transmembrane proteins act as barriers that confine phospholipids and regulate their movement. The findings have implications for understanding the dynamics of lipid organization in cell membranes and the role of the actin-based membrane skeleton in cellular processes.Phospholipids in cell membranes undergo hop diffusion, moving between compartments of 230-nm diameter, confined for 11 ms before hopping to adjacent compartments. This compartmentalization reduces lipid diffusion rates by a factor of 5–100 compared to artificial bilayers. The cell membrane is not compartmentalized by cholesterol-enriched rafts, extracellular matrix, or extracellular domains of membrane proteins, but rather by the actin-based membrane skeleton. Transmembrane proteins anchored to the actin-based membrane skeleton act as rows of pickets, temporarily confining phospholipids through steric hindrance and circumferential slowing. This model explains the observed reduction in lipid diffusion and supports the idea that the cell membrane is compartmentalized with regard to lateral diffusion of phospholipids. DOPE, an unsaturated phospholipid, diffuses rapidly within 230-nm compartments but is slowed when moving between compartments. The NRK cell membrane is doubly compartmentalized, with phospholipids confined in 230-nm compartments and also in larger 750-nm compartments. This double compartmentalization is consistent with the involvement of the actin-based membrane skeleton in lipid diffusion. The results suggest that the actin-based membrane skeleton plays a critical role in regulating lipid diffusion and in the localization of intracellular signals. The study provides evidence for the anchored-protein picket model, in which transmembrane proteins act as barriers that confine phospholipids and regulate their movement. The findings have implications for understanding the dynamics of lipid organization in cell membranes and the role of the actin-based membrane skeleton in cellular processes.