This article presents a systematic review on wearable robotic devices that use human-in-the-loop optimization (HILO) strategies to improve human-robot interaction. A total of 46 HILO studies were identified and divided into upper and lower limb robotic devices. The main aspects from HILO were identified, reviewed, and classified in four areas: 1) human-machine systems; 2) optimization methods; 3) control strategies; and 4) experimental protocols. A variety of objective functions (physiological, biomechanical, and subjective), optimization strategies, and optimized control parameters configurations used in different control strategies are presented and analyzed. An overview of experimental protocols is provided, including metrics, tasks, and conditions tested. Moreover, the relevance given to training or adaptation periods was explored. We outline an HILO framework that includes current wearable robots, optimization strategies, objective functions, control strategies, and experimental protocols. We conclude by highlighting current research gaps and defining future directions to improve the development of advanced HILO strategies in upper and lower limb wearable robots.