Antigen array technologies enable large-scale profiling of the specificity of antibody responses against autoantigens, tumor antigens and microbial antigens. Antibody profiling will provide insights into pathogenesis, and will enable development of novel tests for diagnosis and guiding therapy in the clinic. Recent advances in the field include development of antigen array-based approaches to examine immune responses against antigens encoded in genetic libraries, post-translationally modified proteins, and other biomolecules such as lipids. A promising application is the use of antibody profiling to guide development and selection of antigen-specific therapies to treat autoimmune disease. This review discusses these advances and the challenges ahead for development and refinement of antibody profiling technologies for use in the research laboratory and the clinic.