Background A new generation of medical students, Generation Z (Gen Z), is becoming the predominant population in medical schools and will join the workforce in a few years’ time. Medicine has undergone serious changes in high-income countries recently. Therefore, it is unclear how attractive the medical profession still is for high school students of Gen Z. The aim of this study was to investigate what motivation leads Gen Z students in their choice to study human medicine, and how they see their professional future. Our study was guided by motivation theory and the influence of personality traits and other personal factors on students’ choice of university major. Methods In a cross-sectional online survey, we included third- and fourth-year high school students in Northern Switzerland. We examined the importance of criteria when choosing a university major: personality traits, career motivation, life goals, and other considerations influencing the choice of human medicine versus other fields of study. Results Of 1790 high school students, 456 (25.5%) participated in the survey (72.6% women, mean age 18.4 years); 32.7% of the respondents aspired to major in medicine at university. For all respondents, the foremost criterion for selecting a field of study was ‘interest in the field,’ followed by ‘income’ and ‘job security.’ High school students aiming to study human medicine attached high importance to ‘meaningful work’ as a criterion; supported by 36.2% of those students answering that helping and healing people was a core motivation to them. They also scored high on altruism (p < 0.001 against all groups compared) and intrinsic motivation (p < 0.001) and were highly performance- (p < 0.001) and career-minded (p < 0.001). In contrast, all the other groups except the law/economics group had higher scores on extraprofessional concerns. Conclusions Swiss Gen Z students aspiring to study human medicine show high intrinsic motivation, altruism, and willingness to perform, sharing many values with previous generations. Adequate work-life balance and job security are important issues for Gen Z. Regarding the current working conditions, the ongoing shortage of physicians, and recent findings on physicians’ well-being, the potential for improvement and optimization is high.