Methods for the quantitative comparison of two or more crystal structures are essential for the study of molecular crystals. There are many research areas in which it is necessary to distinguish crystal structures of the same polymorph obtained under different conditions from crystal structures of different polymorphs, as well as to identify and remove duplicate crystal structures from a dataset. Outcomes of the application of accurate and efficient quantitative comparison methods include: (i) improved confidence in polymorph assignment with the inclusion of an objective similarity metric, (ii) rapid interpretation of the results from high-throughput polymorph screening, (iii) curating large databases of crystal structures, (iv) improving the efficiency (and assessing the performance) of methods for first-principles crystal structure prediction, and (v) constructing development and evaluation datasets for machine learning, among others. In this chapter, we review available quantitative metrics, with a focus both on methods based on the comparison of atomic positions and those based on the comparison of powder X-ray diffractograms. Advantages and disadvantages of each class of comparison method are highlighted, and some practical recommendations are made to improve confidence in the results of quantitative crystal structure comparisons.