You can measure free energies. You can measure entropy differences. Entropy itself is pretty slippery. If you don't go down to a quantum level, there's literally no way to say just how much entropy there is in a system, because you can't determine how fine to slice it. (In quantum mechanics, the answer is 'h-bar')

Even if you're aware of quantum mechanics, in many systems there is the question of whether to include degrees of freedom that could possibly become involved but won't (with thermodynamically large probability) on the relevant timescales.