Desirable difficulties are learning conditions that are often experienced as effortful, but have a positive effect on learning results and transfer of knowledge and skills (Bjork & Bjork, 2011; Bjork, 1994). Learners often do not appreciate the beneficial effects of desirable difficulties, and the negative experiences of high effort and perceived low learning make them resistant to engage in desirable difficulties (Biwer et al., 2020a). This ultimately limits learning outcomes and academic achievement. With the increasing emphasis on self-regulation in education, characterized by higher learner agency and abundant choices in what, when, and how to study, the field of educational psychology is in need of theoretical and empirically testable assumptions that improve self-regulation in desirably difficult learning conditions with the aim to foster self-regulation abilities, learning outcomes, and academic achievement. Here, we present a framework that describes how to support self-regulation of effort when engaging in desirable difficulties: the “Start and Stick to Desirable Difficulties (S2D2)” framework. The framework builds on the Effort Monitoring and Regulation model (de Bruin et al., 2020). The aim of this framework is (1) to describe evidence for the central role of perceived effort and perceived learning in (dis)engagement in desirable difficulties, and (2) to review evidence on, and provide an agenda for research to improve learners’ self-regulated use of desirable difficulties to help them start and persist when learning feels tough, but is actually effective.@en