The purpose of the present study was to assess: a) perceived stress, burnout, depression, and empathy at three time points in internal medicine residents, b) the role of gender and trait mindfulness in stress response during residency and c) to evaluate the impact these variables have on performance evaluations. Additionally, specific tasks of the residency that may contribute to the experience of stress and burnout were evaluated to test a model of job strain. Stress predicted subsequent burnout and depression. Burnout predicted subsequent depression, and stress mediated this relationship. Women reported higher mean levels of empathy and burnout than men. The exploratory measure of job strain was not significantly related to stress outcomes. The acting with awareness facet of mindfulness was negatively related to burnout and depression. Performance was both negatively and positively related to stress outcomes. The results are discussed within the context of the current literature.