This chapter develops a generic knowledge-based framework for developing flowsheets for the separation of complex mixtures. The approach relies on generating alternatives taking into account the relation between some characteristic properties of the components and the target assigned for separation, as well as the evaluation of the appropriate separation methods. The task-oriented methodology incites the application of novel techniques. The chapter describes in detail vapour and gas separations, including recent techniques based on exploiting both the size and shape properties and chemical affinities. In the field of liquid separations, the residue curve map technology is a valuable tool for getting thermodynamic insights, namely, for the separations of azeotropes. Enhanced distillation makes use of a mass separation agent, while in hybrid separations, the distillation is combined with other methods, such as liquid-liquid extraction, adsorption, crystallisation, and membranes, or even with reaction.