Background: Involving medical personnel in all aspects of smoking control in the community is indispensable. In a trial to enhance the participation of healthcare professionals in smoking cessation activities; this study was conducted to evaluate knowledge, behavior and attitude of medical school students regarding smoking and substance abuse. Perception of their future role “as physicians” in combating smoking and substance abuse was also explored. Subjects and Methods: A cross- sectional descriptive study was conducted. A self-administered questionnaire based on standardized questionnaires prepared by the World Health Organization covering sections about knowledge, beliefs and practices of the students regarding smoking and substance abuse; was submitted to 296 students enrolled in the Faculty of Medicine of Cairo University, during the academic year 2014-2015. Results: Most of the participants had correct knowledge about health hazards of smoking, where 83.4- 93.6% correctly selected the answers, but still stated that they are in need for courses about this issue. Positive attitudes were also expressed towards smoking legislations and tobacco control policies. Cigarettes and shisha smoking, bango and addictive medications abuse were low among the studied group (13.5, 15.2, 2, 3-6.4%respectively). Conclusion and Recommendations: The prevalence of smoking and substance abuse was relatively low among Cairo University medical students who had generally correct knowledge about the hazards of these practices and positive attitude towards their future role in helping their patients to quit. It may be appropriate to train students about stress management skills through organizing regular “stress coping strategies” sessions to assist them to cope with various stressors and consider implementing counseling programs to support students, especially medical students; the future doctors; who have a leading role in combating smoking and substance abuse in the community.