Cryo-tomography in the electron microscope is unique in its ability to provide high-resolution, three-dimensional structural information about cells, organelles and macromolecules in a nearly native, frozen-hydrated state. However, the phase-contrast imaging method used in conventional cryo-electron tomography fails to faithfully represent the full range of structural features in such specimens. Only certain features are recorded with adequate contrast, and overall contrast is low. The recently developed Zernike phase contrast method has the potential to solve this problem, and here we apply it for the first time to cryo-electron tomography. The new method has uniform transfer characteristics for a wide range of spatial frequencies, leading to improved overall signal-to-noise ratio and raising the prospects of higher resolution and quantitative representation of specimen densities in the reconstructed tomograms. (C) 2010 Elsevier Inc. All rights reserved.