Abstract: In this article, the authors demonstrate the successful design and implementation of synthetic protein switches capable of regulating diverse protein activities like degradation, protein expression, and cellular localization. Importantly, they show that by fine-tuning the binding dynamics of a “key” peptide, an a-helical “latch” and a penta-helical “cage” they can induce conformational changes that allow the switch to transition between On/Off states. Displacement of the “latch” by the “key” peptide causes the exposure of the switch’s functional motifs, thus producing the transition to the On state. These protein switches are successfully implemented both in vivo and in vitro, and more than one switch can be used in tandem. This article is an important milestone in the field of protein design as it describes a potential strategy for generating synthetic proteins whose activity can be directly controlled.