Cancer progression is associated with extensive remodeling of the tumor microenvironment (TME), resulting in alterations of biochemical and biophysical cues that affect both cancer and stromal cells. In particular, the mechanical characteristics of the TME extracellular matrix undergo significant changes. Bioengineered polymer hydrogels can be instrumental to systematically explore how mechanically changed microenvironments impact cancer cell behavior, including proliferation, survival, drug resistance, and invasion. This article reviews studies that have explored the impact of different mechanical cues of the cells’ 3D microenvironment on cancer cell behavior using hydrogel-based in vitro models. In particular, advanced engineering strategies are highlighted for tailored hydrogel matrices recapitulating the TME's micrometer- and sub-micrometer-scale architectural and mechanical features, while accounting for its intrinsically heterogenic and dynamic nature. It is anticipated that such precision hydrogel systems will further the understanding of cancer mechanobiology.