Urine has been steadily gaining popularity as a powerful tool for biomarker discovery as it is easy to collect, non-invasive and available in large quantities. More recently, exosomes have also been identified in urine and its inherent genetic material has proved to reflect an abundant amount of information related to an individual's pathophysiology. Traditional methods of sample handling are simply not robust enough for the molecular analysis required within precision medicine today. Since human urine is one of the most important fluids providing useful information about the body condition, appropriate pre-analytical techniques become critical towards its use within clinical and profiling applications. We discuss the top 6 strategies in sample handling and purification techniques that will lend itself towards the development of a standardized protocol and ultimately, a clean sample fit for investigation.