This article is protected by copyright. All rights reserved optochemical control of biology. In contrast to excellent previous reviews that focus on the chemistry of controlling biological function with light, [1] this review focuses on manipulation of cell and animal biology using photochemical approaches. Purely optogenetic approaches, not utilizing chemical operations, have been reviewed elsewhere. [2] 2. Optical control of small molecules Small molecule probes have been essential tools to perturb and control cellular processes, thereby providing an understanding of detailed biological function. Optical control of small molecule function provides an extra layer of precision to the molecular toolbox by enabling temporal and spatial control with high resolution, as discussed in the examples below. Small molecule protein dimerizers, inhibitors, metabolites, and metal ions have all been rendered lightresponsive through the chemical installation of caging groups and have been applied to the investigation of living systems. In contrast to photocaged nucleic acids, peptides, and proteins, small molecules have the added benefits of being synthetically more accessible and capable of being readily delivered into cells and animals. 2.1. Optical activation of rapamycin induced dimerization Chemical inducers of dimerization (CIDs) are prominent tools for chemical biologists to place biological processes under conditional control. [3] The most commonly utilized CID is rapamycin, which binds to FK506 binding protein (FKBP) and the FKBP-rapamycin binding domain of mTOR (FRB), forming a ternary complex. Due to the small size of FKBP and FRB, these domains have been fused to numerous proteins and subsequent heterodimerization was induced by rapamycin. Processes that have been placed under rapamycin control include Golgi/endoplasmic reticulum association to study mitosis, [4] phosphoinositide control of endocytic trafficking, [5] and inactivation of proteins by rerouting them to the mitochondria. [6] Caged rapamycin analogs allow for placement of these processes under optical control in order to enhance temporal and spatial resolution. The photocaged rapamycin analog 1 was generated through installation of a nitrobenzyl caging group at the C-40 position (Figure 1a). [7] When applied to cells, 1 still induced FKBP-FRB dimerization, indicating that the caging group alone wasn't sufficient to abrogate protein-small molecule interaction, which is consistent with previous modifications at C-40. [8] However, work by the Hahn lab had shown that a truncated FKBP, termed iFKBP, [9] exhibited increased flexibility in the loop that interacts with the C-40 position of rapamycin. This flexibility increased contacts for interaction with 1 and resulted in a distorted binding conformation that prevented formation of the ternary complex consisting of iFKBP, FRB, and 1. This system was then applied to the optical activation of FAK (focal adhesion kinase), using an engineered iFKBP-FAK fusion which rendered the kinase inactive until UV irradiation...