Hormone-refractory prostate cancer is a significant cause of cancer death among American men. Androgen deprivation through surgical or chemical castration is the current treatment for advanced stage prostate cancer. However, the disease invariably relapses with a median of 24 months and is referred to as androgen-independent or castration-resistant prostate cancer (CRPC). The effectiveness of the hormone ablation therapy is limited primarily due to the poor understanding of the molecular mechanisms of disease progression to CRPC stage. Specific chemical modifications of proteins (histones), which package the genetic material or the DNA, control expression of genes that either suppress tumor growth or conversely promote tumor growth. Recent studies have uncovered critical roles for one such chemical modification, histone tyrosine phosphorylation, in genetic integrity and cancer. Important is that, unlike mutations in DNA, these histone modifications are reversible and provide a window for targeted intervention. The role of histone tyrosine phosphorylations in prostate cancer progression is unknown. Identification of specific histone tyrosine phosphorylation events and the enzymes that catalyze the process will facilitate development of new biomarkers for prostate cancer prognosis. This study could also lead to the development of targeted therapeutics against the modifying enzymes in order to suppress resurgence of CRPC and ultimately improve patient survival outcomes.