Light-sheet microscopy enables high-resolution imaging of large, cleared tissues, such as whole brains, but requires careful preparation, mounting, and labeling strategies. In this chapter, we describe the challenges faced by a multi-user imaging facility and the solutions we found for providing access to light-sheet microscopy to users with different research goals. Running such a facility requires strong technical expertise, safety measures, and long-term maintenance yet offers unique advantages for advancing neuroscience and pathology through scalable 3D imaging.