In this paper, we present a component-based multi-level mixed-signal design and simulation methodology that provides a solution to the problem of accurate modeling and simulation of mixed signal, multi-domain (MSMD) systems. This is achieved by first, partitioning the system into components that are modeled by analytic expressions at the behavioral level; and second, integrating these expressions into component behavioral solvers using a combination of piecewise linear (PWL) modeling and Modified Nodal Analysis (MNA). At the system level, a discrete event simulator sends composite signals between these components and manages multiple timescales and feedback. Simulation speed and accuracy can be tuned by controlling the granularity of the regions of operation of the devices, the sample density of optical wavefronts, and the time resolution of the discrete event simulator. The methodology is specifically optimized for loosely coupled systems of complex components such as the ones found in multi-domain microsystems.