Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19 disease, has rapidly imposed an urgent need to identify effective drug candidates. In this context, the high resolution and non-redundant beta-Coronavirus protein cavities database is pivotal to help virtual screening protocols. Furthermore, the cross-relationship among cavities can lead to highlighting multitarget therapy chances. Here, we first collect all protein cavities on SARS-CoV-2, SARS-CoV, and MERS-CoV X-ray structures, and then, we compute a similarity map by using molecular interaction fields (MIFs). All the results come together in CROMATIC (CROss-relationship MAp of CaviTIes from Coronaviruses). CROMATIC encloses both a comprehensive and a non-redundant version of the cavities collection and a similarity map revealing, on the one hand, cavities that are conserved among the three Coronaviruses and, on the other hand, unexpected similarities among cavities that can represent a key starting point for multitarget therapy strategies. Similarity analysis was also performed for the available structures of SARS-CoV-2 spike variants, linking sequence mutations to three-dimensional interaction alterations. The CROMATIC repository is freely available to the scientific community at .