DEFINITIONThe cell is much more than just a bag of protein juice. Indeed, many mechanisms exist in a living cell to keep its contents well organized. One of the most important apparatuses that the cell utilizes to organize the cytoplasm is the cytoskeleton. Therefore, the infl uence of the cytoskeleton on the two -dimensional fl uid of the plasma membrane is an interesting subject. In this chapter, we will focus on this issue, and review the literature about the membrane domains delimited by the part of the actin -based cytoskeleton that is closely opposed to the cytoplasmic surface of the plasma membrane. This part of the cytoskeleton is referred to as the membrane skeleton . Due to its close association with the cytoplasmic surface of the plasma membrane, the membrane -skeleton meshwork directly infl uences the functions of the plasma membrane. As a consequence of the membrane -skeleton meshwork, the plasma membrane is effectively partitioned into mesoscale domains, or compartments, with sizes varying between 30 and 250 nm (with the exception of the larger 750 -nm domain in the doubly nested compartments in normal rat kidney [NRK] cells; Fujiwara et al. 2002 ).We emphasize the characteristic size of these compartments, one to several hundred nanometers, that falls in the mesoscale, where collective dynamics of molecules play critical roles. At this size scale, the number of molecules in the system is insuffi cient for thermodynamics to hold, but is still too big to be tractable for quantum mechanics. In the plasma membrane, there are three types of major mesoscale domains ( meso domains): (1) membrane compartments delineated by the actin -based membrane skeleton; (2) raft domains, where specifi c proteins, glycosphingolipids, and cholesterol are concentrated; and (3) the protein oligomer domains. In this chapter, we will concentrate on the membraneskeleton -induced membrane compartments.Membrane lipids and proteins are both temporarily trapped in these membrane compartments with residency times between 1 ms and 1 second (Kusumi et al. 2005 ). Namely, the two key functional elements of the membrane are both infl uenced by the membrane skeleton, and a growing number of fi ndings support the involvement of the membrane skeleton in many membrane processes (