One approach to achieve localized drug effects is through light control. The use of light to precisely modulate biological pathways has gained attention in recent years. Optical control methods include, among others, photocaged compounds and synthetic photoswitches, which use photochemical isomerization and thermal relaxation processes to alter compound activity, thereby providing precise temporal and spatial control over their effects. In 2020, Trauner and co-workers introduced the first photochemically targeting chimeras (PHOTACs). These molecules are light-activatable PROTACs and consist of a POI ligand, a photoswitch, and an E3 ligase ligand. In their inactive form, PHOTACs prevent ternary complex formation by introducing a steric clash between the binary complex and the second protein (Figure ). When irradiated with light of a specific wavelength, the internal photoswitch changes its conformation, enabling the PHOTAC to form a productive ternary complex (Figure and). This leads to polyubiquitination and subsequent proteasomal degradation of the POI. The active isomer gradually reverts to the inactive form through thermal relaxation, losing its activity, and can also be rapidly inactivated photochemically. This approach could potentially minimize adverse effects, as PHOTACs can be selectively activated by light at the desired location. Their inactivation is also less dependent on clearance and metabolism. Thus, PHOTACs provide a level of spatiotemporal and local control that is unmatched by other targeted protein degradation methods. In this study, we synthesized and characterized a set of three PHOTACs for targeted HDAC6 degradation by incorporating an azobenzene photoswitch, using our previously published HDAC6 PROTAC A6 as a template (Figure ).