The launching of the National Nanotechnology Initiative nearly 4 years ago has captured the scientific and popular imagination and has catalyzed tremendous scientific discovery at an international level. Working with building blocks at the nanometer scale (molecules, nanoclusters, quantum dots, etc.), nanoscale science and engineering promises to alter not only what complex systems we can make, but also how we can make or manufacture systems. Substantial advancements have been made in (1) designing new instrumentation to image and characterize structures at the nanoscale, in (2) computational power and architectures that will allow modeling and simulation of nanostructure properties and performance, in (3) integrating diverse nanoscale building blocks (e.g. biological and electronic materials), and in (4) assembling modest-level nanosystems. The next 'giant steps' in the realization of multifunctional, manufacturable, higher-complexity nanosystems will require substantial improvements in all the areas mentioned above. Complex assembly of new materials will require designing in redundancy and repair into the processes. As more biological/molecular-electronic composite systems are utilized, we will need much a better understanding of information transfer and coherence across biological-electronic material interfaces. The richness of the work done thus far in creating a new Nanotechnology reveals a multitude of outstanding challenges and at the same time opens many avenues for further exploration and applications.