For millions of years, human survival has depended critically on building relationships, seeking social support from others, and sharing resources in groups. This social context has created constant evolutionary pressure to develop specific biological systems designed for face-to-face interaction with physically present others. For only a few years now, we have been living in a rapidly evolving digital world in which social interactions (education, friendship, health care) are shifting to face-to-screen interaction. How does this fundamental shift affect our social interactions? In SODI, we will contrast face-to-face and face-to-screen “live” interactions of many individuals, taking a multi-method, biopsychological approach. According to our theoretical working model, face-to-screen interactions fail to fully engage specific, socially relevant hormonal systems that have evolved to process context-dependent stimuli from face-to-face contact. Consequently, hormone-mediated beneficial social effects should be attenuated, while adding social stimuli should ameliorate this difference. To test the assumptions of our model, we will address three objectives. How do face-to-screen interactions differ from face-to-face ones? Can we “socially enrich” face-to-screen interactions by adding previously lacking social stimuli? Does experimentally modulating hormone levels in the brain affect differences between face-to-face and face-to-screen interactions? In a radically innovative approach, this research combines experimental-psychological interaction paradigms, neurophysiological and subjective measures, and hormone administration to understand the merits and flaws of interacting in a digital reality.