This talk outlines emerging directions in cyber-physical systems such as enhancing sustainability, streamlining transportation, and introducing automation into healthcare and medical applications. A common property of these applications, compared to traditional embedded system examples, such as factory automation, is that humans play a prominent role as an integral part of the overall cyber-physical system whose performance is being optimized. It therefore becomes of interest to understand the role of humans "in the loop" and explore the challenges of accommodating and adapting to human behavior in the design of cyber-physical applications. The talk uses examples of recent research in the area to distill these challenges into a prospective interdisciplinary research agenda on cyber-physical systems with humans in the loop.