Prostate cancer is a gland tumor in the male reproductive system. It is a multifaceted and genomically complex disease. Transmembrane protease, serine 2 and v-ets erythroblastosis virus E26 homolog (TMPRSS2-ERG) gene fusions are the common molecular signature of prostate cancer. Although tremendous advances have been made in unraveling various facets of TMPRSS2-ERG-positive prostate cancer, many research findings must be sequentially collected and re-interpreted. It is important to understand the activation or repression of target genes and proteins in response to various stimuli and the assembly in signal transduction in TMPRSS2-ERG fusion-positive prostate cancer cells. Accordingly, we divide this multi-component review ofprostate cancer cells into several segments: 1) The role of TMPRSS2-ERG fusion in genomic instability and methylated regulation in prostate cancer and normal cells; 2) Signal transduction cascades in TMPRSS2-ERG fusion-positive prostate cancer; 3) Overexpressed genes in TMPRSS2-ERG fusion-positive prostate cancer cells; 4) miRNA mediated regulation of the androgen receptor (AR) and its associated protein network; 5) Quantitative control of ERG in prostate cancer cells; 6) TMPRSS2-ERG encoded protein targeting; In conclusion, we provide a detailed understanding of TMPRSS2-ERG fusion related information in prostate cancer development to provide a rationale for exploring TMPRSS2-ERG fusion-mediated molecular network machinery.