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Motion sickness is a phenomenon attracting increasing attention with the ever-growing popularity of highly automated driving. Understanding motion sickness is of significant interest in the context of self-driven vehicles because, in this case, all occupants of the vehicle are passengers and, therefore, more susceptible to motion sickness. In this article, we report the findings of a study wherein motion sickness was induced in 40% of the participants while driving in real-world conditions. By recording various psychophysiological parameters continuously (electrodermal activity, skin temperature, heart rate, and heart rate variability), we investigate the feasibility of using these to objectively assess motion sickness. Furthermore, the instantaneous physiological reactions of participants to unpleasant driving maneuvers are examined. The changes in the electrodermal activity show a strong correlation with the subjective ratings of motion sickness levels as reported by the participants. The phasic component of the electrodermal activity suggests differences between participants that are susceptible to motion sickness and those who are not. Several driving maneuvers (accelerations, cornering, and driving over speed bumps) were identified as events triggering significant electrodermal responses. These responses could be the result of a mismatch between visual and vestibular perception acting as an aversive, arousing stimulus. While, in this work, the driving maneuvers were partially overlapping and nonuniform, our results pave the way for future investigation of physiological responses to single driving events and their relation to motion sickness with the potential to identify real-time markers of possibly unpleasant driving maneuvers.