This work presents a multi-level method for the design and selection of heat exchange working fluids tailored for Organic Rankine Cycle (ORC) systems used in power and/or heat cogeneration from renewable, low enthalpy sources. A systematic methodology is employed supporting the design of optimum working fluid candidates using Computer Aided Molecular Design (CAMD). The performance of the designed fluids is evaluated using ORC models that enable simulation and economic design optimization. In addition to chemical/physical properties the performed evaluation considers working fluid characteristics such as safety (toxicity and flammability) and environmental properties (ozone depletion potential and global warming potential) that are equally important to economic efficiency. The proposed approach is illustrated through a case study involving varying geothermal field conditions employed as energy sources for greenhouse power and heat co-generation.