Using fully atomistic multislice simulations and molecular-dynamics treatment of proteins in ice, it is shown that multiple electron scattering is important for the interpretation of cryogenic transmission electron microscopy images to achieve atomic resolution in macromolecules. Cryogenic scanning transmission electron microscopy is demonstrated to yield flat contrast transfer over a wide spatial frequency range, such that integrated centre of mass and ptychography are promising methods for future high-resolution microscopy at low dose while providing a high degree of flexibility in post-acquisition data processing.