The regulation of ion channels and transporters by phosphoinositides has received much attention over the past 10 years. There are multiple potential mechanisms for regulation of ion channels and transporters by PIP(2), including a direct binding of PIP(2) to the target proteins, alterations of membrane insertion, and retrieval. Added to the complexities of multiple potential mechanisms is how cells use PIP(2) to regulate so many different processes. Here, I briefly review several past and recent studies to illustrate the complexities and raise outstanding questions for future studies.