Process Systems Engineering (PSE) has effectively solved all major problems in simulation, design, control, diagnosis, scheduling and planning of large-scale chemical processes. As the focus of research moved in scale from cubic metres to cubic millimeters, “plants or labs on a chip” benefited from the accumulated PSE technologies, since the underlying phenomena could still be handled as effective continuous media. Current research, however, has pushed the scale of processing operations to a few nanometers. With the proposition of “nanoscale factories” as the next frontier, PSE must offer new theories and tools to realize the design, fabrication, simulation, operation and control of processing systems. This presentation will address the foundational questions of nanoscale PSE that need to be tackled with new theories and computational methodologies. In particular, we will discuss: (1) How to synthesize the three networks of chemical reactions (process topology; energy production and dissipation system; monitoring and control), which compose the essential design of any nanoscale process, using new views on self-replicating reaction networks. (2) How to fabricate nanoscale structures with desired geometries, using guided self-assembly processes. (3) How to engineer monitoring and control systems, as integral parts of a processing topology, and how to deploy self-regulating control architectures.