The idea that multi-scale dynamic complex systems formed by interacting macromolecules and metabolites, cells, organs and organisms underlie some of the most fundamental aspects of life was proposed by a few visionaries half a century ago. We are witnessing a powerful resurgence of this idea made possible by the availability of nearly complete genome sequences, ever improving gene annotations and interactome network maps, the development of sophisticated informatic and imaging tools, and importantly, the use of engineering and physics concepts such as control and graph theory. Alongside four other fundamental "great ideas" as suggested by Sir Paul Nurse, namely, the gene, the cell, the role of chemistry in biological processes, and evolution by natural selection, systems-level understanding of "What is Life" may materialize as one of the major ideas of biology.