Macromolecules, which adsorb or intrinsically form boundary layers at surfaces sliding past each other in aqueous media, are ubiquitous both in technology and in biological systems and can form effective boundary lubricants. Over the past decade or so, hydration layers robustly bound water molecules that surround charges or zwitterionic groups of different macromolecular species have been identified as remarkable lubricating elements, sustaining high loads while exhibiting a fluid-like response to shear with extremely low friction. This modification of frictional forces in aqueous systems, based on the behavior of water molecules confined to hydration shells, is the central idea behind the hydration lubrication mechanism, which is presented and discussed in detail in the current Perspective. We describe the nature of hydration under confinement and the underlying experiments revealing this mechanism, focusing in particular on synthetic and biological macromolecules attached to surfaces and on phospholipid assemblies. We also emphasize these recent findings in relation to physiological environments and functions of the human body, such as cartilage lubrication, in which hydration lubrication is believed to play an important role.