The study introduces CLARITY, a method to transform intact biological tissue into a transparent, hydrogel-hybridized form that allows for high-resolution imaging and molecular analysis. The technique involves crosslinking tissue with hydrophilic polymers and removing lipids to create a structure that is optically transparent and macromolecule-permeable. This enables detailed imaging of long-range projections, local circuit wiring, cellular relationships, and subcellular structures in intact tissues, including mouse brains and human tissue samples. CLARITY also supports in situ hybridization, immunohistochemistry, and multiple rounds of staining without tissue sectioning, making it suitable for studying both small and large volumes of tissue. The method preserves native molecular information and allows for the analysis of molecular phenotypes in intact systems. The study demonstrates that CLARITY can be applied to various tissues, including human brain samples, enabling the visualization of neurons and their projections in large volumes. The technique also supports subsequent electron microscopy analysis and provides a stable, intact form of tissue for structural and molecular studies. CLARITY has the potential to revolutionize the study of biological systems by enabling the detailed analysis of intact tissues at both structural and molecular levels, offering new insights into the function and disease mechanisms of complex biological systems.The study introduces CLARITY, a method to transform intact biological tissue into a transparent, hydrogel-hybridized form that allows for high-resolution imaging and molecular analysis. The technique involves crosslinking tissue with hydrophilic polymers and removing lipids to create a structure that is optically transparent and macromolecule-permeable. This enables detailed imaging of long-range projections, local circuit wiring, cellular relationships, and subcellular structures in intact tissues, including mouse brains and human tissue samples. CLARITY also supports in situ hybridization, immunohistochemistry, and multiple rounds of staining without tissue sectioning, making it suitable for studying both small and large volumes of tissue. The method preserves native molecular information and allows for the analysis of molecular phenotypes in intact systems. The study demonstrates that CLARITY can be applied to various tissues, including human brain samples, enabling the visualization of neurons and their projections in large volumes. The technique also supports subsequent electron microscopy analysis and provides a stable, intact form of tissue for structural and molecular studies. CLARITY has the potential to revolutionize the study of biological systems by enabling the detailed analysis of intact tissues at both structural and molecular levels, offering new insights into the function and disease mechanisms of complex biological systems.