In this review, we evaluate key molecular pathways and markers of muscle-invasive bladder cancer (MIBC). Overexpression and activation of EGFR, p63, and EMT genes are suggestive of basal MIBC subtype generally responsive to chemotherapy. Alterations in PPARc, ERBB2/3, and FGFR3 gene products and their signaling along with deregulated p53, cytokeratins KRT5/ 6/14 in combination with the cellular proliferation (Ki-67), and cell cycle markers (p16) indicate the need for more radical treatment protocols. Similarly, the "bell-shape" dynamics of Shh expression levels may suggest aggressive MIBC. A panel of diverse biological markers may be suitable for simulation studies of MIBC and development of an optimized treatment protocol. We conducted a critical evaluation of PubMed/Medline and SciFinder databases related to MIBC covering the period 2009-2015. The free-text search was extended by adding the following keywords and phrases: bladder cancer, metastatic, muscle-invasive, basal, luminal, epithelial-to-mesenchymal transition, cancer stem cell, mutations, immune response, signaling, biological markers, molecular markers, mathematical models, simulation, epigenetics, transmembrane, transcription factor, kinase, predictor, prognosis. The resulting selection of ca 500 abstracts was further analyzed in order to select the latest publications relevant to MIBC molecular markers of immediate clinical significance.Vast majority (>90%) of bladder carcinomas that arise from the transitional cells of the bladder mucosal epithelium are noninvasive papillary tumors that are relatively easy to deal with. However, if not detected and treated properly, at least one-third of these cancers ultimately invade the bladder wall and metastize into neighboring organs or lymph nodes by undergoing radical molecular and cellular changes. The resulting muscle-invasive bladder cancer (MIBC) is a heterogeneous group of aggressive epithelial tumors with a high rate of metastasis and poor 5-year survival rate of 30-50%. As noticed by numerous clinical research teams, the number of somatic mutations exhibited by MIBC is notoriously high.