Although the term “systems biology” describes a wide range of diverse research projects, a common feature of systems approaches in biology is that they rely on contributions from various non-biological disciplines. Inspired by Ernst Mayr’s concerns about biological autonomy, this essay explores the status of biology within this evolving, multidisciplinary scientific landscape. After briefly considering competing theoretical views about the optimal role of biology in systems biology, the focus turns on two examples that illustrate distinct strategies for its implementation. On the basis of these examples, I argue that traditional biological concepts remain essential for elucidating meaning from the mathematical models used to represent the experimental results, both in top-down and in bottom-up versions of systems biology. The paper concludes with a discussion of the philosophical implications of the preceding analysis for the normative issue regarding biological autonomy: should biological autonomy be maintained for systems biology to fulfill its aims? The viability of the alternative cannot be excluded a priori. The observed effectiveness of pluralistic explanation in current systems biology, however, suggests that the continuing contributions of an autonomous biology, with its own irreducible concepts and methods, would not obstruct the development of an integrative systems approach but would rather advance its agenda