In this paper, we describe different design methodologies to bridge the gap between 3D and 2D Integrated Circuits in the Electronic Design Automation framework. An extended version of a Die-by-Die place and route flow for 3D systems is presented, focusing on the power management and timing optimization aspects. The corresponding sign-off methodologies to perform 3D power and timing optimization are developed using commercial tools. For both 3D-aware Multi-Die rail analysis and Static Timing Analysis, sample results on a test design example are included as means to validate the flows.