Heat removal and power delivery have become two major reliability concerns in 3D stacked IC technology. For thermal problem, two possible solutions exist: thermal-through-silicon-vias (TTSVs) and micro-fluidic channel (MFC) based liquid cooling. In case of power delivery, a highly complex power distribution network is required to deliver currents reliably to all parts of the 3D stacked IC while suppressing the power supply noise to an acceptable level. However, these thermal and power networks pose major challenges in signal routability and congestion. This is because the signal, power, and thermal interconnects are all competing for routing space. In this paper, we present a co-optimization methodology for the signal, power, and thermal interconnects for 3D stacked ICs based on design of experiments (DOE) and response surface method (RSM). The goal is to improve performance, thermal, noise, and congestion metrics with our holistic approach. We also provide in-depth comparison between T-TSV and MFC based cooling method and discuss how to employ DOE and RSM to best co-optimize the multi-functional interconnects simultaneously.