The work and heat exchange network synthesis problem refers to the problem of determining a network of heat exchangers and pressure equipment that minimize the total annual cost or exergy consumption, where the thermodynamic paths (i.e., pressure-change and temperature-change paths) are variable. In this work, an efficient optimization strategy is presented, consisting of two synthesis phases. In the targeting phase, a novel targeting model is introduced to identify the optimal thermodynamic paths of process streams. The genetic algorithm in the outer level is applied to adjust the streams' temperatures, and the golden section search method in the inner level is used to adjust the hot utility consumption. With the obtained thermodynamic paths, the detailed heat exchanger network is determined using a global search algorithm in the design phase. The integrated methodology is applied to four cases. Except for the illustrating example, results show a decrease of 4.26% in the total annual cost (TAC) for the liquefied natural gas (LNG) example, 48.7% in the TAC for the postcombustion CO2 capture example, and 1.05% in the TAC for the two-stage membrane separation process example.