This paper considers two emerging interdisciplinary, but related topics that are likely to create tipping points in advancing the engineering and science areas. Trusted Autonomy (TA) is a field of research that focuses on understanding and designing the interaction space between two entities each of which exhibits a level of autonomy. These entities can be humans, machines, or a mix of the two. Cognitive Cyber Symbiosis (CoCyS) is a cloud that uses humans and machines for decision-making. In CoCyS, human–machine teams are viewed as a network with each node comprising humans (as computational machines) or computers. CoCyS focuses on the architecture and interface of a Trusted Autonomous System. This paper examines these two concepts and seeks to remove ambiguity by introducing formal definitions for these concepts. It then discusses open challenges for TA and CoCyS, that is, whether a team made of humans and machines can work in fluid, seamless harmony.