Although an established regulator of many cellular functions, the phosphoinositide phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2) appears to have evaded the attention of drug-discovery companies. An increasing number of reports have identified potential links between PtdIns(4,5)P2-mediated signalling pathways and the aetiology of many human diseases. Here, we review current knowledge of the regulation and function of PtdIns(4,5)P2 and discuss how aberrant PtdIns(4,5)P2-mediated signalling might contribute to human pathologies such as cardiac failure, bipolar disorder, channelopathies and the genetic disorder Lowe syndrome.