Recently, there has been a great effort to develop tests based on non-invasive urinary biomarkers (NMIBCs). These tests are based on the fact that NMIBCs are heterogeneous at the molecular level and can be divided into different molecular groups useful to predict prognosis and response to treatment. The assessment of epigenetic alterations, such as DNA methylation, represents a promising cancer biomarker. DNA methylation is an epigenetic modification that affects gene expression without modifying the DNA sequence. Several studies have highlighted the presence of methylated loci in the context of bladder cancer, indicating its potential application as a diagnostic and prognostic biomarker. One of the novel assays based on a DNA methylation profile, the Bladder EpiCheck, analyzes DNA from spontaneous urine, detecting disease-specific DNA methylation patterns in bladder cancer patients. This test, due to its non-invasive nature and highly promising performance could, in future, become an invaluable tool in the follow-up of bladder cancer patients. Potential new applications could include diagnosis and surveillance of upper-tract disease, for the replacement of invasive testing and ureteroscopy.