Plasmid DNA is a potentially effective and safe means of in vivo delivery of exogenous genetic material to human cells and tissues. The lack of physical stability of plasmid formulations however continues to pose major challenges. These formulations tend to aggregate under conditions of interest, especially under physiological ones. Experimental data show that over a period of nearly 30 min after preparation, aggregates of poly-L-lysine-DNA grow to sizes above 1000 nm. This will severely reduce their diffusion rate through tissues and will have a detrimental effect on their uptake by cells. Our theoretical analysis shows that aggregation is a complex function of the physicochemical properties of the system with the initial particle size distribution, solution pH and ionic strength, and temperature being the most important parameters. These considerations show that conditions conducive to the formation of stable formulations are low pH, low ionic strength, a narrow size distribution and low temperature. Though these conditions can not be achieved in vivo they can be maintained during processing and the theoretical analysis lays the foundation for assessment of other complexes that may be able to meet in vivo requirements.