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With the emphasis on research competencies in undergraduate biology education, more students are exposed to course-based research experiences. Undergraduate students who first encounter failure in a biology laboratory course may not always respond appropriately. Little qualitative research has been done to explore students’ responses to failed research. Here we report a case study based on five students’ coping strategies and feelings of confidence while they confront failure in a semester-long investigation of the Hardy-Weinberg Equilibrium with a zebrafish population. All students displayed negative emotions, but their coping strategies varied. Although each student showed a unique research process, all responded with competent, relationship, and autonomous actions as adaptive coping strategies. Support seeking played a critical role to promote their research self-efficacy.