The shape of a cell, the sizes of subcellular compartments and the spatial distribution of molecules within the cytoplasm can all control how molecules interact to produce a cellular behavior. This talk describes how these spatial features can be included in mechanistic mathematical models of cell biology. The Virtual Cell (VCell) computational modeling and simulation software is designed for spatial modeling of cellular reaction-diffusion systems. VCell facilitates choices between physical formulations that implicitly or explicitly account for cell geometry and between deterministic vs. stochastic formulations for biochemical reactions. Recently, we have begun to address the special role of molecular aggregates and clusters in cell biology. New approaches for dealing with the combinatorial complexity associated with interactions of multivalent molecules will be described, including studies on signaling to the actin cytoskeleton.