The search for non-invasive tools for the diagnosis and management of cancer has long been a major goal of cancer research. Cost-effective technologies for blood-based, sensitive and specific detection of nucleic acid biomarkers could potentially transform the way cancer is diagnosed and treated. Circulating microRNAs in blood have recently emerged as clinically useful and minimally invasive predictive, diagnostic and prognostic biomarkers for prostate cancer. However, they are very challenging to detect accurately due to their low concentration and high sequence homology. Herein we highlight the main limitations of the current gold-standard technologies for microRNA detection (including complexity and cost) and discuss recent technological advances toward new blood tests suitable for widespread public screening.