The periodization of resistance exercise is often touted as the most effective strategy for optimizing muscle size and strength adaptations. This narrative persists despite a lack of experimental evidence to demonstrate its superiority. In addition, the general adaptation syndrome, which provides the theoretical framework underlying periodization, does not appear to provide a strong physiological rationale that periodization is necessary. Hans Selye conducted a series of rodent studies which used toxic stressors to facilitate the development of the general adaptation syndrome. To our knowledge, normal exercise in humans has never been shown to produce a general adaptation syndrome. We question whether there is any physiological rationale that a periodized training approach would facilitate greater adaptations compared with nonperiodized approaches employing progressive overload. The purpose of this article is to briefly review currently debated topics within strength and conditioning and provide some practical insight regarding the implications these reevaluations of the literature may have for resistance exercise and periodization. In addition, we provide some suggestions for the continued advancement within the field of strength and conditioning.