Optics involving extremely long, thin sheets of light and a vastly increased Rayleigh range (achieved by breaking the diffraction limit of light sheets of low numerical aperture) allow an elegant application of ultramicroscopy to large samples, such as whole mouse brains or Drosophila. Due to the extremely low divergence of the light sheets, brains can be reconstructed from a single stack of optical sections with nearly isotropic resolution that reaches the single-spine level at higher magnification. Ultramicroscopy can be applied to samples of ever-increasing size. Large pieces of human tumors that have been cleared and stained by a new superfast clearing procedure can be imaged intraoperatively in three dimensions. Optically identified malignancies were subsequently confirmed by standard histological sectioning. We predict that ultramicroscopy of cleared tumors will play an increasingly important role in pathological diagnostics.