Phosphatidylinositol 4,5‐bisphosphate (PIP₂)‐mediated signalling is a new and rapidly developing area in the field of cellular signal transduction. With the extensive and growing list of PIP₂‐sensitive membrane proteins (many of which are ion channels and transporters) and multiple signals affecting plasma membrane PIP₂ levels, the question arises as to the cellular mechanisms that confer specificity to PIP₂‐mediated signalling. In this review we critically consider two major hypotheses for such possible mechanisms: (i) clustering of PIP₂ in membrane microdomains with restricted lateral diffusion, a hypothesis providing a mechanism for spatial segregation of PIP₂ signals and (ii) receptor‐specific buffering of the global plasma membrane PIP₂ pool via Ca²⁺‐mediated stimulation of PIP₂ synthesis or release, a concept allowing for receptor‐specific signalling with free lateral diffusion of PIP₂. We also discuss several other technical and conceptual intricacies of PIP₂‐mediated signalling.