One of the goals for problem-based learning (PBL) is to promote self-regulation. Although self-regulation has been studied extensively, its interrelationships with ill-structured problem solving have been unclear. In order to clarify the interrelationships, this article proposes a conceptual framework illustrating the iterative processes among problem-solving stages (i.e., problem representation and solution generation) and self-regulation phases (i.e., planning, execution, and reflection). The dynamics of the interrelationships are further illustrated with three ill-structured problem-solving examples in different domains (i.e., information problem solving, historical inquiry, and science inquiry). The proposed framework contributes to research and practice by providing a new lens to examine self-regulation in ill-structured problem solving and offering guidelines to design effective tools and strategies to scaffold and assess PBL.