Heavy-duty diesel engine manufacturers, regulators and operators in Europe and US have judged the Selective Catalytic Reduction (SCR) system to be the most suitable exhaust aftertreatment technology to meet the Euro V and US 2010 emission standards for oxides of nitrogen (NOx). The choice of the SCR as the exhaust aftertreatment system has been accompanied by engine calibrations with higher engine-out NOx emissions. Temporary deactivation of the exhaust aftertreatment device, due to malfunction or disrepair could result in excessively high NOx emissions at the tailpipe. Therefore, there is a need to evaluate alternative engine calibrations that would limit in-use NOx emissions during SCR inefficiencies. The objective of this study was to develop and implement a technique to program an engine with different calibrations, which were optimized for exhaust aftertreatment performance. Two very distinct calibrations were evaluated over transient and steady state conditions. The implementation of these calibrations helped meet the emission standards under conditions, which are critical for the SCR operation under real worldconditions, but may not be encountered during the engine certification testing. Multiple calibrations were designed by means of a simple multivariate optimization technique involving the variation of only four engine parameters, namely EGR rate, boost pressure, injection pressure and injection timing. In addition, an empirical model for accurate NOx and fuel consumption (FC) prediction was developed, assuming independency of the parameters. The technique developed in this study was found to be quick to implement, simple and efficient; requiring very little engine test cell time. The main calibrations proved to be engine cycle independent, since comparable emission levels were measured over ESC, FTP and ETC cycles. Low-NOx map was obtained by raising the injection pressure and increasing EGR rates. A NOx emissions reduction of 20% was achieved, with a penalty in fuel economy of less than 3% from the baseline. Several fuel efficient calibrations were generated by advancing injection timing and increasing injection pressure; the highest improvement brought a reduction in FC of more than 6%. Multiple calibrations can be generated by this technique and alternatively used by the engine control system depending upon the thermodynamic conditions of the exhaust stream at the inlet of the SCR system