Cancer is a complex disease that is associated with genetic aberrations and subsequent cellular and noncellular host responses. Tumors harbor diverse cell types that engage in a dynamic interplay to sustain cancer-specific signaling networks. A component of such cellular communication is the production and exchange of various types of extracellular vesicle (EV). Exosomes are small EVs with growing recognition for their role in cancer progression and resistance to therapy. The unique biogenesis of exosomes, their ubiquitous production by all cell types, and their biological features in liquid biopsies have generated excitement for their potential as cancer biomarkers. Researchers from the Northwestern University School of Medicine and MD Anderson Cancer Center discuss the challenges and utility of exosomes as multiparameter biomarker platforms for the detection of cancer. Exosomes reflect heterogeneous biological changes associated with growing tumors, potentially offering a more comprehensive assessment of cancer diagnosis, prognosis, and progression.