Tumor-informed circulating tumor DNA assays detect patient-specific cancer mutations in plasma and hold promise for detecting minimal residual disease (MRD) after or during definitive therapy. Recent large studies across solid tumors and hematologic malignancies suggest that tumor-informed MRD (TI-MRD) is strongly prognostic for relapse and survival. We reviewed disease evidence for these claims, as well as the potential utility in guiding therapeutic decisions. TI-MRD assays consistently achieved high analytical sensitivity. In solid tumors (colorectal cancer [CRC], non-small-cell lung cancer, breast cancer, and bladder cancer), multiple studies demonstrated that post-treatment MRD positivity conferred markedly worse recurrence-free and overall survival. TI-MRD positivity also often preceded clinical or radiological signs of relapse. Studies on hematologic malignancies, such as acute myelocytic leukemia (AML), diffuse large B-cell lymphoma, chronic lymphocytic leukemia (CLL), and multiple myeloma, also demonstrated prognostic power; however, TI-MRD also demonstrated effectiveness in guiding therapy escalation and de-escalation in AML and CLL studies. Ongoing trials in both solid tumors and hematologic malignancies are focused on further evaluating the utility of TI-MRD in guiding therapeutic decisions and enhancing patient survival. TI-MRD testing has matured into a broadly validated prognostic biomarker across multiple cancers supported by large prospective cohorts. Pending results of ongoing randomized trials will clarify its clinical utility in guiding adjuvant therapy. Key challenges remain, including low tumor shedding, assay cost, and standardization. We recommend cautious use of TI-MRD in practice where evidence is strongest (CRC and hematologic malignancies) while awaiting prospective validation in other settings.