Type 2 diabetes is a prototypical complex systems disease that has a strong hereditary component and etiologic links with a sedentary lifestyle, overeating and obesity. Adipose tissue has been shown to be a central driver of type 2 diabetes progression, establishing and maintaining a chronic state of low-level inflammation. The number and diversity of identified endocrine factors from adipose tissue (adipokines) is growing rapidly. Here, I argue that a systems biology approach to understanding the robust multi-level signaling networks established by the adipose secretome will be crucial for developing efficient type 2 diabetes treatment. Recent advances in whole-genome association studies, global molecular profiling and quantitative modeling are currently fueling the emergence of this novel research strategy.