This article provides a brief review of multi-scale modeling at the molecular to cellular scale, with new results for heart muscle cells. A finite element-based simulation package (SMOL) was used to investigate the signaling transduction at molecular and sub-cellular scales (http://mccammon.ucsd.edu/smol/, http://FETK.org) by numerical solution of time-dependent Smoluchowski equations and a reaction-diffusion system. At the molecular scale, SMOL has yielded experimentally-validated estimates of the diffusion-limited association rates for the binding of acetylcholine to mouse acetylcholinesterase using crystallographic structural data. The predicted rate constants exhibit increasingly delayed steady-state times with increasing ionic strength and demonstrate the role of an enzyme's electrostatic potential in influencing ligand binding. At the sub-cellular scale, an extension of SMOL solves a non-linear, reaction-diffusion system describing Ca ligand buffering and diffusion in experimentally-derived rodent ventricular myocyte geometries. Results reveal the important role for mobile and stationary Ca buffers, including Ca indicator dye. We found that the alterations in Ca-binding and dissociation rates of troponin C (TnC) and total TnC concentration modulate subcellular Ca signals. Model predicts that reduced off-rate in whole troponin complex (TnC, TnI, TnT) versus reconstructed thin filaments (Tn, Tm, actin) alters cytosolic Ca dynamics under control conditions or in disease-linked TnC mutations. The ultimate goal of these studies is to develop scalable methods and theories for integration of molecular-scale information into simulations of cellular-scale systems.