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Course-based undergraduate research experiences (CUREs) increase student access to research, providing opportunities for more students to engage with science practices and make novel science contributions. However, little is known about how to teach CUREs effectively. Effective CURE instruction relies on an instructor's knowledge of students, which is used to notice and respond to students as they conduct research. This study investigates CURE instructor knowledge of students that resulted from previous noticing when students experience research challenges. We surveyed a national sample of experienced CURE instructors about the challenges they have seen students experience that are distinctive to CUREs. Analysis from our deductive and inductive qualitative analysis of instructors’ knowledge of students indicated that they paid attention to student struggles in two main areas: nature of science and research as a practice. Instructor interpretations within these two areas provided nuanced insight into their knowledge of students’ knowledge, skills, and emotions across research challenges. Our results provide new insight into CURE instructor knowledge of students that was developed from noticing, which has implications for future research on CURE instruction and instructor professional development.