The phosphoinositide kinase, phosphatidylinositol 4-phosphate 5-kinase (PIP5K), produces the versatile phospholipid phosphatidylinositol 4,5-bisphosphate (PI4,5P₂), through which PIP5K plays crucial roles in a wide variety of cell functions. So far, three PIP5K isozymes and splicing variants have been identified. We speculate that each PIP5K isozyme or splicing variant is activated in a tempo-spatially different manner, due to the existence of activators or recruiters specific to each isozyme: this tempo-spatially different activation of PIP5K produces PI4,5P₂ at different compartments of the cell at different times, which phenomenon may be responsible for the apparent multifunction of PI4,5P₂/PIP5K. Accumulating evidence supports this notion that each PIP5K isozyme is activated by its specific activator and plays a crucial role in a unique cell function. In this article, we describe recent advances regarding the PIP5K isozyme-specific activation mechanisms and physiological functions.