Abstract: As we enter the 21st century, a profound transformation is emerging in the field of computer science and technology, this is also true for the subfield of computer systems. The main characteristic of this transformation is the leap from man-computer symbiosis to man-cyber-physical society (a tri-world of people, computers, and things). This raises four fundamental challenges to computer systems research: 1) we must revisit the very concept of “computation” and “computer system”, and we need to study new workload and usage pattern analytics; 2) we must investigate new metrics of computer systems; 3) we need to explore the possibility of new computer architecture that directly supports network; 4) we need to discover and make use of emergent phenomena. In this paper, based on research work done by oversea researchers and at the Institute of Computing Technology of the Chinese Academy of Sciences, we discuss the four challenges and point out that the answers are still lacking, which may lead to abundant research opportunities.