In recent years, significant information has been accumulated on the molecular alterations that take place during development of transitional cell carcinoma (TCC). A number of studies aimed at defining loss of heterozygosity have shown a general chromosomal instability in TCC with loss of parts of chromosome 9 at early stages of papillomas, and of chromosomes 11, 13, 3, 4, 8, 17 and 18 during further development of the tumor. Oncogenes are activated, exemplified by mutations in the ras gene family and overexpression of the c-erbB-2 gene, in a minor fraction of tumors. Alterations of tumor suppressors (involved in control of the cell cycle, DNA quality control and activation of apoptosis) seem to be frequently involved. Among these p53 has a key role, and one p53 allele is frequently lost in TCC followed by mutation of the remaining allele.These alterations are correlated with survival, disease progression, invasion and recurrence. Also frequently lost are the cell cycle control genes p16 and p15. The predictive value of this has not yet been determined. Studies of glycosylation genes have shown downregulation of the ABO gene, followed by loss of ABO blood group structures and accumulation of the Lewis cell adhesion molecules in high grade tumors. Functional proteome analysis has furthermore identified biomarkers that are correlated with grade and stage. Molecular models for TCC development can now be built, and clinical testing of these is urgently needed.