DNA plays an essential role in nature by carrying the blueprint for life. Despite this prominent position in the “central dogma” of molecular biology, relatively little is known about the molecular-level biophysics of many processes involving DNA. For example, a clear and complete picture of hybridization has yet to be determined. This deficiency in knowledge of DNA behavior has become increasingly poignant in recent years as DNA has been tapped as a solution to problems in a variety of fields of study. Advances in science and technology have made manipulation of genetic information possible; however, for many applications, directing the transport of DNA, and its self-assembly capabilities is not well controlled, leading to poor performance of diagnostics and less than ideal experimental results. In a real sense, the problems facing the use of DNA in new methods and technologies arise from weaknesses in engineering design rather than a fundamental lacking in the biology, but proper engineering is hindered by the lack of unifying models and theories at the molecular level. Due to the large scope of the systems involved, a “one-size-fits-all” simulation approach cannot give the desired answers. Generating solutions to important problems requires the combination of the best models with the most-appropriate simulation techniques. To this end, we previously created and validated a new, coarse grain model of DNA, which showed remarkable predictive capabilities of both the thermal and mechanical properties of the molecule. Since that time, we have expanded the simulation methods used with the model, and leveraged its strengths with those of atomistic representations to better investigate DNA behavior. This presentation will describe these efforts as well as the results for several systems of interest including hybridization, viral packaging of DNA, and factors affecting DNA microarray behavior. The results, taken as a whole, attest to the necessity of flexibility and ingenuity in investigating complex system through simulation.