A mixed-integer non-linear programming optimisation framework is formulated and developed that combines a molecular-based, group-contribution equation of state, SAFT-γγ Mie, with a thermodynamic description of an organic Rankine cycle (ORC) power system. In this framework, a set of working fluids is described by its constituent functional groups (e.g., since we are focussing here on hydrocarbons: single bondCH3, single bondCH2single bond, etc. ), and integer optimisation variables are introduced in the description the working-fluid structure. Molecular feasibility constraints are then defined to ensure all feasible working-fluid candidates can be found. This optimisation framework facilitates combining the computer-aided molecular design of the working fluid with the power-system optimisation into a single framework, thus removing subjective and pre-emptive screening criteria, and simultaneously moving towards the next generation of tailored working fluids and optimised systems for waste-heat recovery applications. SAFT-γγ Mie has not been previously employed in such a framework. The optimisation framework, which is based here on hydrocarbon functional groups, is first validated against an alternative formulation that uses (pseudo-experimental) thermodynamic property predictions from REFPROP, and against an optimisation study taken from the literature. The framework is then applied to three industrial waste-heat recovery applications. It is found that simple molecules, such as propane and propene, are the optimal ORC working fluids for a low-grade (150 °C) heat source, whilst molecules with increasing molecular complexity are favoured at higher temperatures. Specifically, 2-alkenes emerge as the optimal working fluids for medium- and higher-grade heat-sources in the 250–350 °C temperature range. Ultimately, the results demonstrate the potential of this framework to drive the search for the next generation of ORC systems, and to provide meaningful insights into identifying the working fluids that represent the optimal choices for targeted applications. Finally, the effects of the working-fluid structure on the expander and pump are investigated, and the suitability of group-contribution methods for evaluating the transport properties of hydrocarbon working-fluids are considered, in the context of performing complete thermoeconomic evaluations of these systems.