This paper discusses a self-consistent set of modern computational concepts providing an effective approach to the circuit-level harmonic-balance (HB) simulation of nonlinear microwave systems of complex topology. The system is automatically split into the interconnection of a near-optimal number of nonlinear blocks at run time. The resulting structure is then exploited by the domain-partitioning concept. A block-wise constant spectrum is used rather than a common spectrum by considering for each block only the set of spectral lines that are relevant to its electrical function, which leads to a very significant reduction in the number of problem unknowns. System simulation under digitally modulated RF drive is reduced to a sequence of modified multitone HB analyses that are backward coupled through the envelope dynamics. Besides providing high numerical efficiency, this set of techniques opens the way to an effective co-simulation of RF and baseband transceiver sections.