<p>While much is known about the effects of the chemical microenvironment on cellular metabolism, mechanical cues have emerged as critical stimuli of intracellular metabolic pathways. Mechanical signals from the extracellular matrix (ECM), neighboring cells, and the microenvironment intersect with key regulators of cellular metabolism, often leading to changes in fundamental cell behaviors, including cell proliferation and migration. Here, we review recent work that has uncovered a role for mechanical cues from microenvironmental factors on cellular metabolism. We discuss how cell–ECM interactions and forces such as shear, tension, and compression affect cellular metabolic requirements and energy production. Importantly, mechanometabolism shapes both physiological homeostasis and pathological states, and further investigation has implications for understanding tissue function and disease progression and uncovering potential therapeutic strategies.</p>