This chapter presents a system-level design methodology and a use case for modeling and simulation of complex heterogeneous systems based on SystemC and its AMS extensions, SystemC AMS. It follows a bottom-up approach and is composed of two parts. First, the chapter starts with an introduction to the recently standardized SystemC AMS extensions and a short presentation of its currently supported modeling formalisms (MFs) such as timed dataflow (TDF), linear signal flow (LSF), and electrical linear networks (ELNs). Second, a MEMS accelerometer is used as a building block in the SystemC AMS virtual prototype of a complex use case. The chapter shows that the system simulation of a complete wireless sensor network (WSN) that encompasses several domains is actually possible with open source tools, with excellent accuracy compared to traditional commercial tools.