Spherically supported bilayer lipid membranes (SS-BLMs) exhibiting co-existing membrane microdomains were created on spherical silica substrates. These 5 μm SiO2-core SS-BLMs are shown to interact dynamically when interfaced with living cells in culture, while keeping the membrane structure and lipid domains on the SS-BLM surface intact. Interactions between the SS-BLMs and cellular components are examined via correlating fluorescently labeled co-existing microdomains on the SS-BLMs, their chemical composition and biophysical properties with the consequent organization of cell membrane lipids, proteins, and other cellular components. This approach is demonstrated in a proof-of-concept experiment involving the dynamic organization of cellular cytoskeleton, monitored as a function of the lipid domains of the SS-BLMs. The compositional versatility of SS-BLMs provides a means to address the relationship between the phenomenon of lipid phase separation and the other contributors to cell membrane lateral heterogeneity.