This chapter addresses the problem of optimal design and operational planning of multi-echelon, multi-site process supply chain networks (PSCNs) with consideration of responsiveness and profitability. A quantitative characterization of responsiveness for PSCNs is presented, which measures the response time or lead time to changes in demands assuming zero inventories. This measure is incorporated in a multi-period mixed-integer non-linear programming (MINLP) model, which considers the selections of suppliers and manufacturing sites, process technology, production levels and scheduling. The problem is formulated as a bi-criterion optimization model in which the objectives are to maximize the net present value (NPV) and to minimize the lead time. This allows establishing trade-offs between the economics and responsiveness of the supply chain network. The model produces a Pareto-optimal curve, which reveals how the optimal net present value, and therefore the network structure of the PSCN, changes with different specifications of lead time. The application of this model is illustrated through an example. The modeling approach developed in this paper and the results obtained suggest that a new conceptual strategy has been developed that yields useful insights regarding the responsiveness of process supply chain networks.