The treatment of metastatic castration-resistant prostate cancer (mCRPC) is empirical, with progress to a more precision medicine approach hampered by lack of predictive biomarkers. This is due in large part to the historical difficulty of molecularly profiling a bone-predominant metastatic disease. Focus has turned to minimally invasive sources of tumor material to better understand the molecular drivers of therapy resistance. Circulating cell-free tumor DNA (ctDNA) is highly abundant in the bloodstream of mCRPC patients and appears to provide an accurate snapshot of real-time tumor genomics. Already, the analysis of androgen receptor gene alterations in the ctDNA of mCRPC patient cohorts has suggested significant potential for guiding the use of androgen receptor-directed therapy. Furthermore, the monitoring of patient ctDNA burden in the wake of systemic therapy may offer a powerful surrogate for tracking tumor responses and emerging resistant subclones. This seminar covers recent advances in mCRPC patient ctDNA profiling, emerging associations of distinct molecular subtypes with clinical outcomes, and the potential for ctDNA to augment precision oncology.