This review is devoted to the critical analysis of advantages and disadvantages of existing mixture descriptors and their usage in various QSAR/QSPR tasks. We describe good practices for the QSAR modeling of mixtures, data sources for mixtures, a discussion of various mixture descriptors and their application, recommendations about proper external validation specific for mixture QSAR modeling, and future perspectives of this field. The biggest problem in QSAR of mixtures is the lack of reliable data about the mixtures’ properties. Various mixture descriptors are used for the modeling of different endpoints. However, these descriptors have certain disadvantages, such as applicability only to 1 : 1 binary mixtures, and additive nature. The field of QSAR of mixtures is still under development, and existing efforts could be considered as a foundation for future approaches and studies. The usage of non-additive mixture descriptors, which are sensitive to interaction effects, in combination with best practices of QSAR model development (e.g., thorough data collection and curation, rigorous external validation, etc.) will significantly improve the quality of QSAR studies of mixtures.