The critical role of the heterogeneous nature of cellular plasma membranes in transmembrane signal transduction has become increasingly appreciated during the past decade. Areas of relatively disordered, loosely packed phospholipids are disrupted by hydrophobic detergent/carbonate-insoluble glycolipid-enriched raft microdomains (DIGs) of highly ordered (glyco)sphingolipids and cholesterol. DIGs exhibit low buoyant density and are often enriched in glycosylphosphatidylinositol-anchored plasma membrane proteins (GPI proteins), dually acylated signalling proteins, such as non-receptor tyrosine kinases (NRTKs), and caveolin. At least two types of DIGs, hcDIGs and lcDIGs, can be discriminated on basis of higher and lower content, respectively, of these typical DIGs components. In quiescent differentiated cells, GPI proteins and NRTKs are mainly associated with hcDIGs, however, in adipose cells certain insulin-mimetic stimuli trigger redistribution of subsets of GPI proteins and NRTKs from hcDIGs to lcDIGs. Presumably, these stimuli induce displacement of GPI proteins from a GPI receptor located at hcDIGs whereas simultaneously NRTKs dissociate from a complex with caveolin located at hcDIGs, too. NRTKs are thereby activated and, in turn, modulate intracellular signalling pathways, such as stimulation of metabolic insulin signalling in insulin-sensitive cells. The apparent dynamics of DIGs may provide a target mechanism for regulating the activity of lipid-modified signalling proteins by small drug molecules, as exemplified by the sulfonylurea, glimepiride, which lowers blood glucose in an insulin-independent fashion, in part.