As the use of clear aligners in orthodontic practice has increased significantly, interproximal reduction is frequently recommended, and is included in the planning of most cases. At the current stage of development of virtual planning, indications for locations in which to perform interproximal reduction do not consider local factors that may interfere with or even contraindicate the procedure, such as sensitivity, the occurrence of previous interproximal reduction and shape/size discrepancy. Interproximal reduction is an invasive and irreversible procedure, and must therefore be planned and executed in such a way as to re-anatomise the crowns, giving them macro- and microscopic characteristics similar to natural ones. The present article aims to shed light on some of the most important factors related to the use of interproximal reduction in clinical practice, especially when associated with clear aligner treatment, so that the treatment goals can be achieved with minimal risk of harm.