Laser ablation has found numerous applications in biomedical and industrial settings but has not spread as quickly as a means of cleaning artwork. In this Account, we report recent advances in the study and application of laser cleaning to the conservation of cultural heritage. We focus on the solution of representative cleaning problems of encrusted stones, metals, and wall paintings that were achieved through the optimization of laser pulse duration. We begin by introducing the basic mechanisms involved in the laser ablation of stratified materials and the criteria for preventing undesired side effects to the substrate and then briefly present case studies for each of these materials. Laser interaction effects are reviewed in a schematic way, with a concise overview of the physical models needed to support intuitive interpretations of the phenomenology observed, both in laboratory tests and in practical applications on important artifacts. This approach aims to provide keys of generalization that will favor the rigorous application of laser cleaning, repeatability of the successful results reported in this work, and further dissemination and acceptance of the technique. The topics treated examine the ablation mechanisms along with the efficiency, gradualness, selectivity, and effectiveness of the technique as a function of the pulse duration of neodymium laser systems and the operating conditions. Physical modeling and experimental evidence support the selection of pulse durations of between several tens of nanoseconds and several tens of microseconds, making it possible to minimize the risk of photothermal and photomechanical effects and maximize the selectivity of the ablation process. The sections dedicated to stones and metals also deal with the important problem of discoloration, which has significantly slowed the spread of the laser cleaning technique. The well-known problem of a yellowish appearance after laser cleaning is shown to be closely related to the ablation process; it can therefore be prevented by a suitable selection of irradiation parameters. The metal surfaces investigated are amalgam gilding, gold leaf gilding, and, for the first time, silver artifacts. We also describe the criteria used for applying laser ablation techniques to restoring unique masterpieces, such as Lorenzo Ghiberti's Porta del Paradiso and Donatello's David. Furthermore, a novel and unusual cleaning approach for archaeological silver is reported. Based on underwater laser irradiation, it provides a way to prevent oxidative effects and amplify the photomechanical coupling to the hard, thick concretions that usually accompany archaeological pieces. Finally, the experimental extension of the laser cleaning approach to wall painting and its practical use in important restoration works is presented. The practical examples reveal a significant advance in perspective for the application, which was unthinkable until recently. In sum, this Account describes novel technological and methodological contributions of laser cleaning that are having a significant impact in the field of cultural heritage conservation.