Profilins are small actin-binding proteins that are essential in all organisms that have been examined to date. In vitro, profilins regulate the dynamics of actin polymerization, which is their key role in vivo during cell motility. However, there is growing evidence that, apart from actin binding, profilins function as hubs that control a complex network of molecular interactions. Profilins interact with a plethora of proteins and the importance of this aspect of their function is just beginning to be understood. In this article, I will summarize recent findings in mammalian cells and mice, and discuss the evidence of a role for profilins in cellular processes such as membrane trafficking, small-GTPase signaling and nuclear activities, in addition to neurological diseases and tumor formation.