This commentary discusses the potential role of p-glycoprotein (Pgp) on the gastrointestinal absorption and cellular transport of dietary cholesterol. This is currently a controversial issue due to the conflicting evidence about the role of this ABC transporter in cholesterol transport. During the preparation of this commentary, several key publications on this topic arguing for and against this mechanism have been published. If true, this mechanism of Pgp could represent a novel role for Pgp and provide a potentially new molecular target for drug design and development.