In three experiments, we examine the role of motives underlying goal pursuit and the metacognitive strategy of mental contrasting with implementation intentions (MCII) to predict the strategic use of self-regulation responses (persistence, disengagement, and reengagement) when faced with attainable, unattainable, or multiple goals. We trained half of the participants to use MCII and treated the rest as control. Experiment 1 (N = 261) underscored the role of autonomous motivation in nurturing adaptive cognitive appraisals and coping mechanisms, which facilitated persistence and progress with a difficult but attainable goal. In contrast, controlled motives undermined striving by predicting threat appraisals and giving up coping. MCII training ameliorated the negative impact of controlled motivation on goal striving by reducing threat appraisals. In Experiment 2 (N = 391), we manipulated the task to make the initial goal unattainable. Strategic goal striving (disengagement from the unattainable goal followed by reengagement with an alternative goal) was facilitated by MCII and autonomous goal motives, and culminated in increases in positive affect. In Experiment 3 (N = 432), we extended these findings to a multiple-goal setting. The research further develops the literatures on self-regulation and self-determination, while having implications for life domains where individuals pursue multiple and/or difficult goals. © 2022 The Authors. Journal of Applied Social Psychology published by Wiley Periodicals LLC.