Abstract Definitions are proposed for the independent and joint contributions that the chemical groups A and B make to the free energy of association of the ligand A− B with a receptor. The definitions are independent of the choice of the standard state and are consistent with the basic thermodynamic cycle relating the association of the ligands A− B, A− Y and X− B to the receptor Rappaport 1976. The basic idea is the use of the excess free energy of association of the ligand A− Y over the free energy of association of the reference ligand X− Y as the measure of the “independent” contribution of the group A to the binding. This definition allows the free energy of association of the ligand A− B to be written as the sum of the independent contributions of the groups A and B, their joint contribution, and an invariant free energy of association of the reference ligand with any receptor. With the appropriate definition of the receptor-reference ligand complex, water can be chosen as the reference ligand. Using ΔG( A−OH)− AG(HOH), ΔG(H− B−H)− ΔG(HOH) and ΔG(HO− C)− ΔG(HOH) as the definitions of the “independent” contributions of the chemical groups A, B and C to the binding of the ligand A− B− C, the joint contribution of the groups A and C to the binding is ΔG( A− B− C) − ΔG( A− B− H) − ΔG(H- B- C) + ΔG(H− B−H).