Mission- and safety-critical domains are more and more characterized by interactive and multimedia systems varying from large-scale technologies (e. g. airplanes) to wearable devices (e. g. smartglasses) operated by professional staff or volunteering laypeople. While technical availability, reliability and security of computer-based systems are of utmost importance, outcomes and performances increasingly depend on sufficient human-machine interaction or even cooperation to a large extent. While this i-com Special Issue on “Human-Machine Interaction and Cooperation in Safety-Critical Systems” presents recent research results from specific application domains like aviation, automotive, crisis management and healthcare, this introductory paper outlines the diversity of users, technologies and interaction or cooperation models involved.