Dual-fuel low-temperature combustion is a possible solution for alleviating the tradeoff between oxides of nitrogen and soot emissions in conventional diesel combustion, albeit with poor combustion stability, high carbon monoxide, and unburned hydrocarbon emissions at low engine loads. The present work compares emissions and combustion (heat release and other metrics) of both diesel and poly-oxy methylene dimethyl ether as high-reactivity fuels to ignite natural gas while leveraging spray-targeted reactivity stratification, which involved multiple injections of the high-reactivity fuels. The experiments included six parametric sweeps of: (1) start of first injection, (2) start of second injection, (3) percentage of energy substitution of natural gas, (4) commanded injection duration ratio, (5) rail pressure, and (6) intake pressure. The experiments were performed on a 1.8 L heavy-duty single-cylinder research engine operating at a medium speed of 1339 rev/min. Not-to-exceed limits for the indicated oxides of nitrogen emissions, maximum pressure rise rate, and the coefficient of variation of the indicated mean effective pressure were set to 1 g/kWh, 10 bar/CAD, and 10%, respectively. The indicated emissions decreased and combustion improved significantly for both fueling combinations when the experimental procedure was applied.