To increase range of motion, physical therapists frequently use passive stretch as a means of gaining increased excursion around a joint. In addition to clinical studies showing effectiveness, thereby supporting evidence-based practice, the basic sciences can provide an explanation how a technique might work once a technique is known to be effective. The goal of this article is to review the potential cellular events that may occur when muscle fibers are stretched passively. A biomechanical example of passive stretch applied to the ankle is used to provide a means to discuss passive stretch at the cellular and molecular levels. The implications of passive stretch on muscle fibers and the related connective tissue are discussed with respect to tissue biomechanics. Emphasis is placed on structures that are potentially involved in the sensing and signal transduction of stretch, and the mechanisms that may result in myofibrillogenesis are explored.