Increasing efforts to minimize global warming has led to regulation of greenhouse gas (GHG) emissions of automotive applications. The US is frontrunner regarding implementation of GHG related legislation with the introduction of GHG phase 1 and phase 2, ultimately targeting a 40% fuel consumption reduction in 2027 compared to 2010 on vehicle level. More specific, engines are required to reduce CO2 emissions by 5% compared to GHG phase 1 levels. Next to the GHG emission legislation, more stringent legislation is anticipated in the US to further reduce NOx emissions: a further 90% reduction is targeted as soon as 2024 compared to 2010 standard. Meeting these anticipated ultra-low NOx standards within the GHG phase 2 constraints on CO2 forms a great challenge. This paper presents an overview of the main challenges and key aspects regarding meeting ultra-low NOx requirements within the constraints on CO2 and N2O set by GHG phase 2 regulations. The study is based on simulation results from validated control-oriented models of current and future engine and aftertreatment technologies. As reference a Heavy-Duty EURO VI compliant engine and aftertreatment system is used, applying a conventional diesel combustion process. On engine level, application of Waste Heat Recovery (WHR) and Variable Valve Actuation (VVA) – in form of an Electronically Opening and Closing Valve EOCV - are evaluated to reduce the impact of ultra-low NOx requirements on fuel consumption. Considered aftertreatment technologies contain SCR on Filter and Passive NOx adsorber in combination with (multi-point) model-based dosing control logic. Tailpipe NOx and engine-out CO2 levels are evaluated on both US and European type-approval cycles. Based on the results a view on future Heavy Duty engines compliant to next generation legislation will be presented. As a further outlook also the application of advanced low temperature combustion concepts and use of CO2 neutral and sustainable fuels will be discussed.