This paper describes a number of new system of systems engineering (SoSE) issues that must be addressed in order to design and deploy a safe, secure, and private informatics infrastructure for remote patient monitoring systems that are interoperable with the emerging U.S. National Healthcare Information Network (NHIN). Motivations for NHIN's ambitious remote patient monitoring goals–such as reducing the cost of care and improving medical care quality for chronically ill patients–are introduced, and the technological requirements and challenges that arise are described. This paper demonstrates the use of SoSE modeling, simulation, verification and validation techniques similar to the emerging draft of INCOSE's SoSE Engineering Guide to improve the success of such projects. The tools used include event driven modeling and software simulation tools to assist in the design and evaluation of predictive software models that simulate key safety and performance aspects of proposed remote patient monitoring systems.