Chemical programming of the temperature domains of existence of liquid crystals is greatly desired by both academic workers and industrial partners. This contribution proposes to combine empirical approaches, which rely on systematic chemical substitutions of mesogenic molecules followed by thermal characterizations, with a rational thermodynamic assessment of the effects induced by chemical perturbations. Taking into account the similarities which exist between temperature-dependent cohesive Gibbs free energy densities (CFEDs) and pressure–temperature phase diagrams modeled with the Clapeyron equation, chemical perturbations are considered as pressure increments along phase boundaries, which control the thermotropic liquid crystalline properties. Taking the familiar calamitic amphiphilic cyanobiphenyl-type mesogens as models, the consequences of (i) methyl substitution of the aromatic polar heads and (ii) connections of bulky silyl groups at the termini of the apolar flexible alkyl chain on the melting and clearing temperatures are quantitatively analyzed. Particular efforts were focused on the translation of the thermodynamic rationalization into a predictive tool accessible to synthetic chemists mainly interested in designing liquid crystals with specific technological applications.