Automotive industry is driven by economic and legislative constraints to increase fuel efficiency and reduce CO2-emissions to a certain extend. To reach the required threshold values, manufacturers consider waste heat recovery by means of Organic Rankine Cycle (ORC) in passenger cars and heavy-duty trucks. This work deals with the crucial issue of identifying an optimal working fluid which is flexible in terms of application and condensing temperature and which is applicable in real systems. For this purpose, a large-scale screening based on computational chemistry and thermodynamic process simulation is coupled with a multi-criteria evaluation. In total, about 72 million chemical substances provided by the PubChem database are screened and more than 3000 promising candidates are evaluated considering COSMO-RS based thermodynamic data as well as constructional, regulatory and security aspects. Five promising working fluids are identified and it is shown that these fluids outperform widely discussed candidates like synthetic refrigerants. Even more remarkably is the fact that within the TOP 100 working fluids only twelve have already been reported in ORC literature. However, the optimal set of working varies as it depends on configuration (with and without mass flow splitting) and condensing temperature. In general, the study demonstrates that a large-scale screening of the complete chemical space can reveal unconventional working fluids for thermodynamic cycles.