Low temperature combustion through in-cylinder blending of gasoline and diesel offers the potential to improve engine efficiency while yielding low engine-out soot and NOx emissions. This investigation utilized 3-D KIVA combustion simulation to guide the development of viable dual-fuel low temperature combustion strategies for heavy-duty applications.Model-based combustion optimization was performed at 1531rpm and 11 bar BMEP for a 12.4 L heavy-duty truck engine. Various engine operating parameters were explored through design of experiments (DoE). The parameters involved in the optimization process included compression ratio, air-fuel ratio, EGR rate, gasoline-to-diesel ratio, and diesel injection strategy (i.e., single-diesel injection vs. two-diesel injections, diesel injection timings, and the split ratio between two-diesel injections). Optimal cases showed near zero soot emissions and very low NOx emissions. Moreover, fuel consumption was improved 11-13% over baseline diesel operation. Compared to a compression ratio of 16, a compression ratio of 14 was found to require a lower gasoline-to-diesel ratio and provide improved fuel consumption. Suitable diesel injection strategies and recommended air system targets were identified.