Optimal 3D spatial packaging of interconnected systems with physical interactions (thermal, hydraulic, electromagnetic, etc.), or SPI2, plays a vital role in the functionality, operation, energy usage, and life cycle of practically all engineered systems, from 3D chips to ships to aircraft. These highly-nonlinear SPI2 problems, involving tightly constrained component packing, governed by coupled physical phenomena transferring energy and material through intricate geometric interconnects, have largely resisted design automation for decades, and can quickly exceed human cognitive abilities at even moderate complexity levels. Existing design methods treat the pieces of this problem separately without a fundamental systems approach and are sometimes too slow to evaluate various possible designs. Hence, there exists an emergent need to develop efficient SPI2 design automation frameworks for two reasons: 1) to enable the rapid generation and evaluation of candidate SPI2 design solutions; and 2) for the development of newer complex engineering systems. In this paper, the holistic 3D-SPI2 design problem with its attributes is defined, previous research efforts in various individual SPI2 related areas are reviewed, some existing critical gaps are outlined, and associated challenges are identified. Finally, a vision for fundamental research in SPI2 design based on the authors' experience in this topic is presented through a set of new exciting opportunities at the intersection of several engineering domains.