Gene editing technologies help identify the genetic perturbations driving tumour initiation, growth, metastasis and resistance to therapeutics. This wealth of information highlights tumour complexity and is driving cancer research towards precision medicine approaches based on an individual's tumour genetics. Bladder cancer is the 11th most common cancer in the UK, with high rates of relapse and low survival rates in patients with muscle-invasive bladder cancer (MIBC). MIBC is highly heterogeneous and encompasses multiple molecular subtypes, each with different responses to therapeutics. This evidence highlights the need to identify innovative therapeutic targets to address the challenges posed by this heterogeneity. CRISPR-Cas9 technologies have been used to advance our understanding of MIBC and determine novel drug targets through the identification of drug resistance mechanisms, targetable cell-cycle regulators, and novel tumour suppressor and oncogenes. However, the use of these technologies in the clinic remains a substantial challenge and will require careful consideration of dosage, safety and ethics. CRISPR-Cas9 offers considerable potential for revolutionizing bladder cancer therapies, but substantial research is required for validation before these technologies can be used in the clinical setting. [Abstract copyright: © 2024. Springer Nature Limited.]