This work presents the first approach to the systematic design and selection of optimal working fluids for Organic Rankine Cycles (ORCs) based on computer aided molecular design (CAMD) and process optimization techniques. The resulting methodology utilizes group contribution methods in combination with multi-objective optimization technology for the generation of optimum working fluid candidates. Optimum designs of the corresponding ORC processes are then developed for the comprehensive set of molecules obtained at the CAMD stage, in order to identify working fluids that exhibit optimum performance in ORCs with respect to important economic, operating, safety and environmental indicators. The proposed approach is illustrated with a case study in the design of working fluids for a low-temperature ORC system. Particular attention is paid to safety and environmental characteristics such as flammability, toxicity, ozone depletion and global warming potential. The methodology systematically identified both novel and conventional molecular structures that enable optimum ORC process performance.