X-ray diffraction plays a pivotal role in understanding of biological systems by revealing atomic structures of proteins, nucleic acids, and their complexes, with much recent interest in very large assemblies like the ribosome. Since crystals of such large assemblies often diffract weakly (resolution worse than 4 Å), we need methods that work at such low resolution. In macromolecular assemblies, some of the components may be known at high resolution, while others are unknown: current refinement methods fail as they require a high-resolution starting structure for the entire complex 1. Determining such complexes, which are often of key biological importance, should be possible in principle as the number of independent diffraction intensities at a resolution below 5 Å generally exceed the number of degrees of freedom. Here we introduce a new method that adds specific information from known homologous structures but allows global and local deformations of these homology models. Our approach uses the observation that local protein structure tends to be conserved as sequence and function evolve. Cross-validation with R free determines the optimum deformation and influence of the homology model. For test cases at 3.5 – 5 Å resolution with known structures at high resolution, our method gives significant improvements over conventional refinement in the model coordinate accuracy, the definition of secondary structure, and the quality of electron density maps. For re-refinements of a representative set of 19 low-resolution crystal structures from the PDB, we find similar improvements. Thus, a structure derived from low-resolution diffraction data can have quality similar to a high-resolution structure. Our method is applicable to studying weakly diffracting crystals using X-ray micro-diffraction 2 as well as data from new X-ray light sources 3. Use of homology information is not restricted to X-ray crystallography and cryo-electron microscopy: as optical imaging advances to sub-nanometer resolution 4, 5, it can use similar tools.