Autonomous and Adaptative Cyber-Physical Systems (ACPS) represent a new knowledge frontier of converging “nano-bio-info-cogno” technologies and applications. ACPS have the ability to integrate new `mutagenic’ technologies, i.e., technologies able to cause mutations in the society. Emerging approaches, such as artificial intelligence techniques and deep learning, enable exponential speedups for supporting increasingly higher levels of autonomy and self-adaptation. In spite of this disruptive landscape, however, deployment and broader adoption of ACPS in safety-critical scenarios remains challenging. In this paper, we address some challenges that are stretching the limits of ACPS safety engineering, including tightly related aspects such as ethics and resilience. We argue that a paradigm change is needed that includes the entire socio-technical aspects, including trustworthiness, responsibility, liability, as well as the ACPS ability to learn from past events, anticipate long-term threads and recover from unexpected behaviors.