Pancreatic ductal adenocarcinoma (PDAC) features a prominent stromal microenvironment with remarkable cellular and spatial heterogeneity that meaningfully impacts disease biology and treatment resistance. Recent advances in tissue imaging capabilities, single-cell analytics, and disease modeling have shed light on organizing principles that shape the stromal complexity of PDAC tumors. These insights into the functional and spatial dependencies that coordinate cancer cell biology and the relationships that exist between cells and extracellular matrix components present in tumors are expected to unveil therapeutic vulnerabilities. We review recent advances in the field and discuss current understandings of mechanisms by which the tumor microenvironment shapes PDAC pathogenesis and therapy resistance.