loading . . . 3D imaging with enhanced transparency, signal-to-background ratios, and antigen detection using HyPer-3D Choi et al. develop HyPer-3D, a technique that enhances 3D imaging of cleared organs by significantly increasing signal-to-background ratios, optical clearing capacity, and visualization of poorly recognized antigens and fluorescent reporters. HyPer-3D enables enhanced, high-contrast multiplex interrogation of complex tissue architectures across experimental models, including human specimens, with improved signal discernability. http://dlvr.it/TRq3cP