The possibility of selecting the working fluid of a closed power cycle represents one of the most important levers to maximise the efficiency and to optimise the design of this technology. This chapter is intended to provide a description of the present state of knowledge on the effects that fluid thermo-physical properties, such as molecular complexity and molecular mass, have on the design and performance of cycle components. With a view to allow for accounting for multicomponent inert and reactive working fluids along the optimisation process, the chapter then presents the main outstanding scientific barriers which need to be overcome.