The strong need for the discovery of novel disease markers together with the development of high-throughput techniques that provide highly sensitive analysis of protein content in tissues and bodily fluids, using proteomics, has opened the completely new chapter in biomarker discovery. The detection of biomarkers based on urinary proteome analysis is rapidly advancing and may provide new tools to improve non-invasive diagnostics, prognostics, and therapy enhancement. As a tool for biomarker discovery, urinary proteomics is especially fruitful in the area of early diagnostics and differentiation of renal damage, and it possesses enormous potential for improving and expanding non-invasive cancer diagnostics. An abundance of urinary proteins could provide a wide variety of biomarkers for the diagnosis and follow-up of many systemic diseases as well. This article reviews the utility of urinary proteomics for biomarker discovery from the perspective of clinical application. Despite huge potential and prompt development of urinary proteomics, many challenges are still in front of us. Research effort and financial investment have to be oriented on providing strategies for exceeding current methodological and technical obstacles in a way to ensure the successful validation and implementation of newly discovered urinary biomarkers. The result is expected to be the development of new non-invasive tests and procedures able to guarantee higher efficiency of patient care and provide needed personalized medical approach.