SPOP (Speckle-type POZ protein) encodes a Cullin 3-based E3-ubiquitin ligase that has several substrates, including the androgen receptor (AR), and steroid receptor coactivator 3 (SRC-3). Upon SPOP mutation in prostate cancer, impaired ubiquitination of its substrates can lead to enhanced AR signaling and cell proliferation. Both AR and AR coactivators are substrates deregulated by SPOP mutation, providing a possible explanation for the associated increase in AR activity seen in this subtype of prostate cancers. SPOP mutations exclusively occur in ETS-negative group of prostate cancer. ERG ubiquitination is also regulated by SPOP. ERG fusion proteins evade SPOP-mediated degradation. This might explain the reason for mutual exclusivity of ETS fusion and SPOP mutation in prostate cancer and create a potential novel therapeutic avenue for ETS fusion tumors. SPOP mutant are significantly associated with CHD1 deletions at 5q21 or 6q21 regions. CHD1 gene controls the transcriptional activity across the genome. It is recurrently deleted in 10%-25% of primary and metastatic prostate cancer, and particularly focal homozygous deletions are restricted to ETS-negative tumors. The SPOP-mutant/CHD1-deleted subset of prostate cancer have characteristic molecular features, including high levels of DNA methylation, homogeneous gene expression patterns, distinct somatic copy-number alterations (SCNA), as well as frequent overexpression of SPINK1 mRNA. The latter is associated with aggressive disease and increased risk of biochemical recurrence. The SPINK1 may act through EGFR pathway, hence, EGFR inhibitors may have therapeutic role in SPINK1-postive prostate cancer.