Prostate cancer is the second most common malignancy in men worldwide, and incidence is likely to rise in the next decade. Screening options are limited as this has been shown to result in over-treatment of clinically insignificant disease. New biomarkers and technologies to detect them are therefore needed in order to better diagnose and stratify patients in primary care. Circulating cell-free DNA (ccfDNA) has gained interest as a potential minimally invasive biomarker, detectable in many bodily fluids (such as blood, urine, and cerebral spinal fluid) and reflecting the mutational landscape in tumours. More recently, the size distribution of ccfDNA fragments has also gained interest as a specific biomarker, where differences in size distribution have been observed between healthy volunteers and cancer patients, resulting in the new field of fragmentomics. Analysis of ccfDNA sizes provides avenues for alternative analytical technologies but commercial options are currently limited. Most focus on mutation detection and are subject to several biases that may affect size distribution. Here we discuss the available technologies and identify major issues and considerations that may affect their implementation as a clinically useful test based on ccfDNA size profiling.