Heat shock proteins (HSPs) and clusterin (another chaperone protein with HSP-like properties) are present in normal cells and are upregulated by cellular stressors such as hyperthermia, hypoxia, and cytotoxic agents. HSPs are overexpressed in a wide range of cancers. Cancer cells are in a constant state of proteotoxic stress and exploit the HSPs to protect themselves against the toxic effects of aberrant oncoproteins, genomic instability, hypoxia, and acidosis. In many patients with cancer, high levels of HSPs are associated with poor prognosis and treatment resistance as these proteins protect tumour cells from therapeutic stressors such as androgen or oestrogen withdrawal, radiation, and cytotoxic chemotherapy. Differences in the expression levels of HSPs in bladder cancers compared with normal urothelium have led to HSPs being investigated as diagnostic and prognostic biomarkers. Evidence suggests that HSPs are important modulators of the immune system and have a role in BCG-stimulated regression of urothelial cancers. New bladder cancer treatment strategies that target HSPs are being investigated and could have a synergistic role with modern radiotherapy and chemotherapy regimens. A combination of OGX-427 (an antisense oligonucleotide that targets HSP27), gemcitabine, and cisplatin is currently being investigated in a phase II trial of patients with advanced bladder cancer.