Life has been found to flourish at extreme pressures (above 1 kbar), implying that adaptations have been made so the proteins in the organism can function. Our studies are on both genetic adaptations of the proteins as well as modifications of the intracellular environment to protect against pressure, using molecular dynamics computer simulations and high-pressure experiments including SANS and SAXS. Here, the focus is on how some organic osmolytes also appear to be “piezolytes” that protect proteins against pressure. For instance, sharks and rays use a mixture of urea, a protein denaturant, and trimethylamine N-oxide (TMAO), a protein stabilizer, as osmolytes. Interestingly, shallow species have a ratio of urea to TMAO that is known to lead to counteraction of their effects on protein stability but the proportion of TMAO increases linearly with depth of the species. This has led to the proposition that TMAO is a piezolyte, although the mechanism is not clear. Our studies of urea and TMAO in aqueous solution show that TMAO lengthens the lifetime of hydrogen bonds in the solution by increasing the viscosity. Since our studies of the enzyme dihydrofolate reductase as well as pure water indicate that an effect of pressure is to shorten hydrogen bond lifetimes, this suggests that the piezolyte activity of TMAO is by increasing the lifetimes. Moreover, this leads to a model based on solute-water and water-water hydrogen bond lifetimes that can be used to describe the denaturing/stabilizing effects of urea and TMAO in terms of preferential interaction and exclusion.