The methodologies advocated in computational biology are in many cases proper system-level approaches. These methodologies are variously connected to the notion of “mesosystem” and thus on the focus on relational structures that are at the basis of biological regulation. Here, I describe how the formalization of biological systems by means of graph theory constitutes an extremely fruitful approach to biology. I suggest the epistemological relevance of the notion of graph resides in its multilevel character allowing for a natural “middle-out” causation making largely obsolete the traditional opposition between “top-down” and “bottom-up” styles of reasoning, so fulfilling the foundation dream of systems science of a direct link between systems analysis and the underlying physical reality.