The development of fractional photothermolysis has revolutionized the treatment of skin scarring, rejuvenation, and tightening. By creating targeted microthermal zones and leaving surrounding tissue intact, this concept has provided the field with efficacious results, with less downtime and a better safety profile. This has started to change the paradigm of what is considered first-line treatment for scarring and rejuvenation. While originally applied to nonablative lasers, fractionation has now been employed in ablative, quality-switched, picosecond, and novel hybrid fractional lasers. Furthermore, other energy-based technologies, such as radiofrequency, have adopted the concept of fractionation in an attempt to optimize the balance of efficacy, downtime, and side effects. Herein, we describe how the ever-expanding repertoire of fractional devices is applied to the treatment of scarring, skin rejuvenation, and tightening. In addition, newer applications, such as transdermal drug delivery, are being developed by using fractional devices. Growing experience with these devices has broadened their relevance to more skin types and body sites than ever. Ultimately, the knowledge of appropriate treatment parameters is paramount and allows for the safe and effective treatment of a variety of patients with numerous devices.