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Simple Summary The field of liquid biopsy is rapidly evolving. Techniques that improve accuracy are constantly being developed, and clinicians increasingly use liquid biopsy as a tool to guide their clinical practice. The assessment of minimal or microscopic residual disease (MRD) after oncological treatment with curative intent, however, remains challenging. Therefore, the implementation of liquid biopsy to determine the presence of MRD is not yet standardized. In this review, we focus on the detection of MRD through liquid biopsy in solid cancers, highlighting currently available methodologies and ongoing challenges. Abstract One reason why some patients experience recurrent disease after a curative-intent treatment might be the persistence of residual tumor cells, called minimal residual disease (MRD). MRD cannot be identified by standard radiological exams or clinical evaluation. Tumor-specific alterations found in the blood indirectly diagnose the presence of MRD. Liquid biopsies thus have the potential to detect MRD, allowing, among other things, the detection of circulating tumor DNA (ctDNA), circulating tumor cells (CTC), or tumor-specific microRNA. Although liquid biopsy is increasingly studied, several technical issues still limit its clinical applicability: low sensitivity, poor standardization or reproducibility, and lack of randomized trials demonstrating its clinical benefit. Being able to detect MRD could give clinicians a more comprehensive view of the risk of relapse of their patients and could select patients requiring treatment escalation with the goal of improving cancer survival. In this review, we are discussing the different methodologies used and investigated to detect MRD in solid cancers, their respective potentials and issues, and the clinical impacts that MRD detection will have on the management of cancer patients.