ABSTRACT This proposal seeks to obtain a Luxendo MuVi Light Sheet Microscope (LSM) with an environmental control unit to be housed in the Light Microscopy Shared Resource Labs (SRLs) of the University of Rochester Medical Center (URMC) as a shared equipment jointly supported by the Multiphoton and Analytical Imaging Center (MAGIC) and the Center for Advanced Light Microscopy and Nanoscopy (CALMN). This microscope would greatly expand and enhance the imaging capabilities of both imaging centers to fulfill the increasing needs of fast three- dimensional imaging of delicate live specimens as well as large cleared tissues from the diverse user groups. Nowadays, researchers are interested in a more complete picture of their studied models with higher degrees of multiplexing and throughput, while our current imaging systems are insufficient to fully capture the three-dimensional characteristics of samples in fast and gentle manners. Bringing in the LSM technique will significantly benefit many current health-related research programs at URMC, which include studies on Influenza, CAR-T therapy, COVID-19, Spinal Cord Injury, Autism etc., by significantly improving the spatial and temporal imaging capabilities. The technological breakthroughs using light sheet microscopy will advance those health-related research with better understandings of the intricate dynamics and structures of cells within living and intact specimens. High resolution fluorescence imaging has proven an invaluable and central tool for the advancement of biomedical discoveries. The URMC Light Microscopy SRLs have seen a rapid growth in the last three years with the join of two experienced directors introducing three new cutting-edge imaging instruments that have greatly enhanced the community’s funded research activities. Acquisition of a light sheet microscope will add new impetus to establishing a state-of- the-art comprehensive imaging resource at the URMC and the upstate New York that will continuously provide scientists new avenues for bearing on fundamental questions pertaining to human diseases. Additionally, by leveraging the local data and computational resources, the Light Microscopy SRLs will maximize the impact of the light sheet microscopy technique that can be widely adopted by various research programs to further promote and advance biological discoveries.