Objectives: Little is known about specific personal and professional factors influencing student distress. The authors conducted a comprehensive assessment of how learning environment, clinical rotation factors, workload, demographics and personal life events relate to student burnout. Methods: All medical students (n = 3080) at five medical schools were surveyed in the spring of 2006 using a validated instrument to assess burnout. Students were also asked about the aforementioned factors. Results: A total of 1701 medical students (response rate 55%) completed the survey. Learning climate factors were associated with student burnout on univariate analysis (odds ratio [OR] 1.36-2.07; all P ≤ 0.02). Being on a hospital ward rotation or a rotation requiring overnight call was also associated with burnout (ORs 1.69 and 1.48, respectively; both P ≤ 0.02). Other workload characteristics (e.g. number of admissions) had no relation to student burnout. Students who experienced a positive personal life event had a lower frequency of burnout (OR 0.70; P ≤ 0.02), whereas those who experienced negative personal life events did not have a higher frequency of burnout than students who did not experience a negative personal life event. On multivariate analysis personal characteristics, learning environment and personal life events were all independently related to student burnout. Conclusions: Although a complex array of personal and professional factors influence student well-being, student satisfaction with specific characteristics of the learning environment appears to be a critical factor. Studies determining how to create a learning environment that cultivates student well-being are needed. © Blackwell Publishing Ltd 2009.