Residence time (RT) refers to the duration that a drug remains bound to its target, affecting its efficacy and pharmacokinetic properties. RTs are key factors in drug design, yet the structure-based design of ligands with desired RTs is still in its infancy. Here, we propose that a combination of cutting-edge molecular dynamics-based methods with classical computer-aided ligand design can help identify ligands that bind not only with high affinity to their target receptors but also with the required residence time to fully exert their beneficial action without causing undesired side effects.