Package and PCB-system aware IC co-design and verification entail early awareness of the impact of signal integrity, power integrity, timing, and electromagnetic interference (EMI) impact on functionality and performance. Higher frequencies, along with stringent EMC regulations, are driving the need for developing EMI-aware design methodologies in early and sign-off phases of design cycles. This article discusses the significant challenges of scale, connectivity, turnaround time, and accuracy needed in developing such a flow. In particular, the numerical effect of violating established EMI guidelines is quantified in the flow, enabling cutting-edge designs that are less conservative and still satisfy EMI constraints. The role of rigorous large-scale 3D full-wave electromagnetic simulation in developing such a full-system EMI prediction and early design flow is discussed. © 2011 Wiley Periodicals, Inc. Int J RF and Microwave CAE, 2012.