Urothelial bladder cancer is a common cancer associated with considerable burden for both patients and healthcare providers alike. The majority of patients present with non-muscle-invasive bladder cancer (NMIBC) which, although not immediately life-threatening, requires appropriate initial management and long-term surveillance which is both invasive and costly. Accurate diagnostic urinary biomarkers could be transformational in this setting, yet have proved to be a significant challenge to bladder cancer scientists over the last two decades. Such biomarkers would need to represent a range of tumour grades and stages, encompass inter- and intra-tumour heterogeneity, and compete with the current diagnostic gold standard of cystoscopy with a sensitivity and specificity of 85% and 87%, respectively. For the field to move forward in this current exciting era of high-throughput proteomics and genomics, bladder cancer scientists need to find a consensus on the optimal urinary substrate (DNA, RNA, protein, etc) and deliver robust well-designed studies in the correct populations with appropriate statistical input. Issues relating to tumour heterogeneity and anticipatory diagnosis also require considerable thought. The challenge remains unchanged.