Protein and nucleic acids footprinting using x-rays to generate hydroxyl radicals as the footprinting reagent has unique power to interrogate the structure and dynamics of macromolecules in solution and in the cell.  Nucleic acids footprinting technologies and applications using radiolysis emerged nearly 30 years ago but protein studies, enabled by sensitive mass spectrometry instruments have more recently been developed and disseminated.  This has resulted in a myriad of published studies, and has driven development of x-ray footprinting studies at the synchrotron (with programs at the National Synchrotron Light Source and the Advanced Light Source) and has stimulated complementary footprinting technologies used in investigator laboratories across the world. As footprinting provides a pure measure of solvent accessibility for reactive residues in macromolecules (e.g. local structural information) additional data is needed to provide the tertiary and quaternary structure context (e.g. global structural information) for interpreting the high-resolution data provided by the technique. Thus, it is natural to integrate data from techniques like macromolecular crystallography, cross-linking, and small angle x-ray scattering with footprinting, using a range of computational approaches. Going forward the frontier of footprinting science will emphasize assessing the structure and dynamics of macromolecular assemblies in physiological contexts including living cells. New beamline developments at ALS and the NSLS-II will enable these exciting new studies.