Phosphatidylinositol 4,5-bisphosphate is a multi-functional lipid, whose proposed functions now number more than twenty, covering many aspects of cell biology in several different subcellular compartments. The enzymes primarily responsible for synthesizing this lipid, the Type I phosphatidylinositol 4-phosphate 5-kinases, are therefore a tightly regulated and diverse family. Here we review our current knowledge about these enzymes and how they may be regulated.