X-PLOR is a highly sophisticated computer program that provides an interface between theoretical foundations and experimental data in structural biology, with specific emphasis on X-ray crystallography and nuclear magnetic resonance spectroscopy in solution of large biological macro-molecules. This manual to X-PLOR Version 3.1 presents the theoretical background, syntax, and function of the program and also provides a comprehensive list of references and sample input files with comments. It is intended primarily for researchers and students in the fields of computational chemistry, structural biology, and computational molecular biology.