Twenty-first century opportunities for GSI will be governed in part by a hierarchy of physical limits on interconnects whose levels are codified as fundamental, material, device, circuit, and system. Fundamental limits are derived from the basic axioms of electromagnetic, communication, and thermodynamic theories, which immutably restrict interconnect performance, energy dissipation, and noise reduction. At the material level, the conductor resistivity increases substantially in sub-50-nm technology due to scattering mechanisms that are controlled by quantum mechanical phenomena and structural/morphological effects. At the device and circuit level, interconnect scaling significantly increases interconnect crosstalk and latency. Reverse scaling of global interconnects causes inductance to influence on-chip interconnect transients such that even with ideal return paths, mutual inductance increases crosstalk by up to 60% over that predicted by conventional RC models. At the system level, the number of metal levels explodes for highly connected 2-D logic megacells that double in size every two years such that by 2014 the number is significantly larger than ITRS projections. This result emphasizes that changes in design, technology, and architecture are needed to cope with the onslaught of wiring demands. One potential solution is 3-D integration of transistors, which is expected to significantly improve interconnect performance. Increasing the number of active layers, including the use of separate layers for repeaters, and optimizing the wiring network, yields an improvement in interconnect performance of up to 145% at the 50-nm node.