Although not a new concept, the use of quantitative analysis in biological networks has stimulated renewed interest under the umbrella of Systems Biology. The common hope is that the use of mathematical analysis would enable quantitative prediction in Biology. However, this promise has not been realized in the past attempts of mathematical efforts. Given the history, what needs to be done differently to ensure the success of Systems Biology? This talk will attempt to address this issue and demonstrate that the fusion (seamless integration) between biology and engineering is essential. This fusion should occur both at the practical problem-solving and philosophical reasoning levels. In particular, we will draw examples developed in our laboratory to demonstrate this point. These include metabolic engineering, regulatory analysis, and synthetic biology.