A new optimization method for the synthesis of nonisothermal reactor networks offers major challenges concerning the lack of robustness in the existing methods and the numerous local and near-optimal solutions that characterize these problems. The approach offers a reliable and widely tested methodology that upholds a profile-based search. The search concentrates on targets rather than network details. The results illustrate ways to avoid unnecessarily complicated networks and develop simpler and transparent designs. The single-phase examples explain merits over past studies and other conventional synthesis methods. Multiphase examples are presented for the first time in the literature, as well as results from an industrial example.