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A primary goal of personalized medicine is to develop tumor-specific biomarkers to aid in treatment selection and to better evaluate response to targeted therapies. The assessment of circulating blood markers as surrogate real-time biopsies of disease status, termed liquid biopsies, has been under investigation. There are many different types of liquid biopsies each with different functionalities and limitations. These include tumor markers, circulating tumor cells, cell-free DNA, and extracellular vesicles including exosomes. Multiple clinical trials have evaluated liquid biopsies as prognostic biomarkers with positive results. Additional studies are underway to evaluate liquid biopsies as predictive biomarkers, pharmacodynamic biomarkers, and surrogate efficacy endpoints for treatment response evaluation. There are several challenges in and barriers to implementation of liquid biopsies into clinical trials and subsequently into routine clinical practice, which are addressed in this review.