Training of the trunk or core muscles for enhanced health, rehabilitation, and athletic performance has received renewed emphasis. Instability resistance exercises have become a popular means of training the core and improving balance. Whether instability resistance training is as, more, or less effective than traditional ground-based resistance training is not fully resolved. The purpose of this review is to address the effectiveness of instability resistance training for athletic, nonathletic, and rehabilitation conditioning. The anatomical core is defined as the axial skeleton and all soft tissues with a proximal attachment on the axial skeleton. Spinal stability is an interaction of passive and active muscle and neural subsystems. Training programs must prepare athletes for a wide variety of postures and external forces, and should include exercises with a destabilizing component. While unstable devices have been shown to be effective in decreasing the incidence of low back pain and increasing the sensory efficiency of soft tissues, they are not recommended as the primary exercises for hypertrophy, absolute strength, or power, especially in trained athletes. For athletes, ground-based free-weight exercises with moderate levels of instability should form the foundation of exercises to train the core musculature. Instability resistance exercises can play an important role in periodization and rehabilitation, and as alternative exercises for the recreationally active individual with less interest or access to ground-based free-weight exercises. Based on the relatively high proportion of type I fibers, the core musculature might respond well to multiple sets with high repetitions (e.g., >15 per set); however, a particular sport may necessitate fewer repetitions.