While conceptually promising for the field of polymer mechanochemistry, the piezomechanical cycle has yet to be realized experimentally. The major obstacle to an experimental implementation is that the piezomechanical cycle requires hydrostatic conditions at the molecular level. However, in experiments on (bulk) polymers, realizing such conditions is far from straightforward. On the contrary, pressure is a common way of inducing mechanophore activation and the general problem of non-hydrostaticity at the molecular level has been pointed out. In the case of the bisanthracene mechanophore, for example, XP-PCM simulations have helped rationalize pressure-induced bond rupture via a leverage principle. To understand mechanical bond cleavage and formation events in functional polymers and the intricate interplay between hydrostatic and anisotropic conditions at the molecular level, multiscale simulation techniques need to be developed and applied to a range of different systems. Such sophisticated computational tools will allow researchers to exploit the full potential of polymer mechanochemistry and help shed light on the mechanical and high-pressure behavior of molecules embedded in crystals or surrounded by other complex environments.