Oligo- and polysaccharides are infamous for being extremely flexible molecules, populating a series of well-defined rotational isomeric states under physiological conditions. Characterization of this heterogeneous conformational ensemble has been a major obstacle impeding high-resolution structure determination of carbohydrates and acting as a bottleneck in the effort to understand the relationship between the carbohydrate structure and function. This challenge has compelled the field to develop and apply theoretical and experimental methods that can explore conformational ensembles by both capturing and deconvoluting the structural and dynamic properties of carbohydrates. This review focuses on computational approaches that have been successfully used in combination with experiment to detail the three-dimensional structure of carbohydrates in a solution and in a complex with proteins. In addition, emerging experimental techniques for three-dimensional structural characterization of carbohydrate–protein complexes and future challenges in the field of structural glycobiology are discussed. The review is divided into five sections: (1) The complexity and plasticity of carbohydrates, (2) Predicting carbohydrate–protein interactions, (3) Calculating relative and absolute binding free energies for carbohydrate–protein complexes, (4) Emerging and evolving techniques for experimental characterization of carbohydrate–protein structures, and (5) Current challenges in structural glycoscience.