A dramatic shift in system complexity is occurring, bringing monolithic system designs to be progressively replaced by modular approaches. In the latest years, this trend has been emphasized by the system of systems (SoS) concept, in which a complex system or application is the result of the integration of many independent, autonomous constituent systems (CS), brought together in order to satisfy a global goal under certain rules of engagement. The overall behavior of the SoS, emerging from such complex interactions and dependencies, poses several threats in terms of dependability, timeliness, and security, due to the challenging operating and environmental conditions caused by mobility, wireless connectivity, and the use of off-the-shelf components. Referring to our experience in mobile safety-critical applications gained from three different research projects, in this paper, we illustrate the challenges and benefits posed by the adoption of an SoS approach in designing, developing, and maintaining mobile safety-critical applications, and we report on some possible solutions.