The successful integration of precision diagnostics with new personalized therapies opens numerous doors to improve the management of a variety of diseases. In cancer, tissue-environmental features of tumor progression and invasion, including aberrant extracellular matrix remodeling, stromal composition changes, and immune cell engagement, create engineering opportunities for use in developing novel biomarkers and therapeutic targets. In this seminar, I will focus on an emerging paradigm in precision diagnostics: synthetic biomarkers. These bioengineered sensors harness microenvironment-dependent activation mechanisms to generate molecular reporters that can be read out in biofluids. To overcome the limitations often associated with molecular disease biomarkers (cross-reactivity with healthy tissues, dilution in biofluids below detectable levels, and rapid degradation of released material), I have engineered next-generation synthetic biomarker platforms with enhanced specificity and clinical actionability by 1) developing CRISPR-Cas-amplifiable urinary reporters to detect and differentiate disease states at the point-of-care; 2) advancing theranostic technologies to precisely target the hallmarks of cancer metastasis in specific tissues; 3) improving noninvasive in vivo imaging capabilities to allow for rapid assessment of disease status and interventional efficacy over time. Collectively, these studies highlight the use of chemical tools with built-in cancer-reactive modules, embracing a vision for precision health through integrated strategies: identification/monitoring, imaging, and intervention in a personalized manner.