After the successful structural analysis of the human and other organisms’ genomes the last decade witnessed a fundamental shift in the area of research in molecular biology: the move into Omics. It produced a plethora of data that require methodological and conceptual approaches to systematize, integrate, and interpret data which go beyond a linear understanding of biological processes and systems. The promise of the rapidly developing field of systems biology is to extend—if not overcome—the methodological and theoretical limits set by previous research undertaken in molecular biology. Taking this contemporary development seriously, this chapter investigates the framing of basic epistemic concepts (life, system, reductionism, holism, and model) by scientists working in systems biology. Based on a corpus of written evidence and interviews conducted with system biologists in Germany, we analyze the metaphorical frameworks underlying their conceptualization to tackle implicit meanings and the practical relevance ascribed to them. It becomes apparent that (to some extent) different professional backgrounds bear an impact on the framing of different concepts and heterogeneous interpretation prevails. The results underline the need for theoretical clarification of basic epistemic concepts in systems biology and the implementation of a science philosophy curriculum as a basic ingredient of university education. Both aspects are important to avoid methodological and theoretical fallacies that restrict the innovative potential of systems biology.