Reggie-1/flotillin-2 and reggie-2/flotillin-1 are ubiquitously expressed, well-conserved proteins that are associated with membrane microdomains known as rafts. Studies from us and others have suggested a role in various cellular processes such as insulin signaling, T cell activation, membrane trafficking, phagocytosis, and epidermal growth factor receptor signaling. Recent findings also demonstrate that reggie-1 is associated with cell motility and transformation. However, the exact function of reggie proteins remains to be clarified. In this review, we will focus on some recent findings that have shed new light on the elusive molecular function of these highly interesting proteins. We will especially discuss the emerging role of reggie proteins in membrane receptor signaling and membrane trafficking, with emphasis on the regulation of the molecular function of reggies by post-translational modifications such as phosphorylation and lipid modifications.