Mindset theory describes a context-dependent belief systemon thedegree that intelligence can change with effort. Students'chemistry mindsets may predict students' behavioral responsesto challenges they experience within a chemistry course. This studywas designed to investigate whether challenges mediate the relationshipbetween chemistry mindset and academic performance. 745 first-semestergeneral chemistry students participated in the study. The studentswere surveyed on their mindset at the beginning and challenges theyexperienced through the end of the semester. Factor analyses wereperformed to characterize commonalities in students' perceptionof challenges, and structural equation modeling was used to examinewhether challenges mediate the relationship between chemistry mindsetand academic performance. To gain more insight, students reportingfixed and growth mindsets were compared regarding challenges and howchallenges relate to their final grades. Analysis of data revealedthat challenges can be perceived in concert with others, which resultedin three fundamental challenges: individual challenges, teaching-relatedchallenges, and chemistry-related challenges. Chemistry-related challengesmediated the relationship between mindset and academic performance.Further, students reporting a growth mindset and earning a grade ofC+ or lower rated the three fundamental challenges as relatively high.These challenges may explain why some students who report a growthmindset can earn a low grade. Among students reporting a fixed mindsetearning a grade of C+ or lower, only chemistry-related challengeswere rated highly. Understanding the nature of challenges and theirrole in success provides potential opportunities to modify instructionto support all students' success in chemistry.