Phosphatidylinositol 4,5-bisphosphate (PIP(2))-mediated signalling is a new and rapidly developing area in the field of cellular signal transduction. With the extensive and growing list of PIP(2)-sensitive membrane proteins (many of which are ion channels and transporters) and multiple signals affecting plasma membrane PIP(2) levels, the question arises as to the cellular mechanisms that confer specificity to PIP(2)-mediated signalling. In this review we critically consider two major hypotheses for such possible mechanisms: (i) clustering of PIP(2) in membrane microdomains with restricted lateral diffusion, a hypothesis providing a mechanism for spatial segregation of PIP(2) signals and (ii) receptor-specific buffering of the global plasma membrane PIP(2) pool via Ca(2+)-mediated stimulation of PIP(2) synthesis or release, a concept allowing for receptor-specific signalling with free lateral diffusion of PIP(2). We also discuss several other technical and conceptual intricacies of PIP(2)-mediated signalling.