One goal in neuroscience is to dissect neuronal connections within the nervous system in health and disease. To accomplish this, neurons and their extensions need to be imaged and followed in the entire brain and spinal cord. While non-invasive imaging methods such as MRI do not have sufficient resolution to trace individual cells, standard histology – serial tissue sectioning and tracing in consecutive sections – is time consuming and prone to mistakes. Here, we review an alternative method called “3D imaging of solvent cleared organs” or “3DISCO” that can achieve high-resolution imaging of neuronal connections in several millimeters of depth without tissue sectioning. 3DISCO is fast: imaging of an entire organ at a cellular resolution can be completed within a few hours. 3DISCO is versatile: it is applicable to various tissues including the spinal cord, brain, lung, mammary glands, immune organs and tumors; it can be executed using various microscopy techniques, including light-sheet, widefield epifluorescence, confocal, 2-photon, light microscopy and optical coherent tomography. Here, we review the application of 3DISCO along with other popular clearing and imaging methods, their limitations and the obstacles that remain.