Polyacrylamide (PAAm) hydrogels are widely adopted as 2D‐model soft substrates for investigating cell‐material interactions in a controlled in vitro environment. They offer facile synthesis, tunable physico‐chemical properties, diverse biofunctionalization routes, optical transparency, mouldability in a range of geometries and shapes, and compatibility with living cells. PAAm hydrogels can be engineered to reconstruct physiologically relevant biointerfaces, like cell‐matrix or cell–cell interfaces, featuring biochemical, mechanical, and topographical cues present in the extracellular environment. This Review provides a materials science perspective on PAAm material properties, fabrication, and modification strategies relevant to cell studies, highlighting their versatility and potential to address a wide range of biological questions. Current routes are presented to integrate cell‐instructive features, such as 2D patterns, 2.5D surface topographies, or mechanical stiffness gradients. Finally, the recent advances are emphasized toward dynamic PAAm hydrogels with on‐demand control over hydrogel properties as well as electrically conductive PAAm hydrogels for bioelectronics.