Science, technology, engineering, and mathematics (STEM) courses are considered to be challenging for students and may present unique challenges for each domain. This study addresses a gap in the research literature by investigating the challenges students face in general and organic chemistry lecture courses. Students provided information regarding their perceptions of success or failure in the face of challenges. Survey responses were used to examine the types of challenges students commonly face in chemistry. Frequencies of challenge types were compared across groups of students who perceived themselves as either having overcome their challenge or not. A significant difference in performance was observed for these two groups across the semester. One specific challenge, chemistry ability, was identified as relevant to mindset theory, was more prevalent among students who did not overcome their challenges, and showed decreased performance relative to other challenges. Students experience a wide range of challenges in chemistry courses, and these interact with their mindset and impact their performance. Modifications to instruction can address many of these challenges and encourage persistence toward success.