The extracellular matrix (ECM) plays a crucial role in regulating tissue development and homeostasis, and its dysregulation contributes to neoplastic progression. The ECM not only serves as a scaffold for tissue organization but also provides critical biochemical and biomechanical cues that guide cell growth, survival, migration, and differentiation, as well as modulating vascular development and immune function. The hallmarks of cancer, defined by Hanahan and Weinberg, encompass key biological capabilities essential for the development, growth, and dissemination of human cancers, including sustained proliferation, evasion of growth suppression, death resistance, replicative immortality, induced angiogenesis, initiation of invasion, dysregulation of cellular energetics, avoidance of immune destruction, and chronic inflammation. This review argues that biophysical and biochemical cues from the tumor-associated ECM influence each of these cancer hallmarks and are critical for malignancy. The success of cancer prevention and therapy programs requires a deep understanding of the reciprocal feedback between the evolving ECM, tumor cells, and their associated stromal cells. The ECM's influence on tumor progression is multifaceted, affecting cell proliferation, evasion of growth suppressors, resistance to cell death, replicative immortality, angiogenesis, invasion, metastasis, immune evasion, and metabolic reprogramming. The ECM's stiffness and composition can modulate these processes, making it a potential therapeutic target. However, the ECM's heterogeneity within tumors and its complex interactions with various cell types pose significant challenges in developing effective therapeutic strategies. Further research is needed to elucidate the precise mechanisms by which the ECM influences cancer progression and to identify optimal therapeutic interventions.The extracellular matrix (ECM) plays a crucial role in regulating tissue development and homeostasis, and its dysregulation contributes to neoplastic progression. The ECM not only serves as a scaffold for tissue organization but also provides critical biochemical and biomechanical cues that guide cell growth, survival, migration, and differentiation, as well as modulating vascular development and immune function. The hallmarks of cancer, defined by Hanahan and Weinberg, encompass key biological capabilities essential for the development, growth, and dissemination of human cancers, including sustained proliferation, evasion of growth suppression, death resistance, replicative immortality, induced angiogenesis, initiation of invasion, dysregulation of cellular energetics, avoidance of immune destruction, and chronic inflammation. This review argues that biophysical and biochemical cues from the tumor-associated ECM influence each of these cancer hallmarks and are critical for malignancy. The success of cancer prevention and therapy programs requires a deep understanding of the reciprocal feedback between the evolving ECM, tumor cells, and their associated stromal cells. The ECM's influence on tumor progression is multifaceted, affecting cell proliferation, evasion of growth suppressors, resistance to cell death, replicative immortality, angiogenesis, invasion, metastasis, immune evasion, and metabolic reprogramming. The ECM's stiffness and composition can modulate these processes, making it a potential therapeutic target. However, the ECM's heterogeneity within tumors and its complex interactions with various cell types pose significant challenges in developing effective therapeutic strategies. Further research is needed to elucidate the precise mechanisms by which the ECM influences cancer progression and to identify optimal therapeutic interventions.