Abstract. Lineage plasticity and histologic transformation from prostate adenocarcinoma to neuroendocrine prostate cancer (NEPC) occurs in up to 15-20% of patients with castration-resistant prostate cancer (CRPC) as mechanism of treatment resistance and is associated with aggressive disease and poor prognosis. NEPC tumors typically display small cell carcinoma morphology with loss of androgen receptor (AR) expression and gain of neuroendocrine (NE) lineage markers. However, there is a spectrum of phenotypes that are observed during the lineage plasticity process, and the clinical significance of mixed histologies or those that co-express AR and NE markers or lack all markers is not well defined. Translational research studies investigating NEPC have used variable definitions making clinical trial design challenging. Here we discuss the diagnostic workup of metastatic biopsies to help guide the reproducible classification of phenotypic CRPC subtypes. We recommend classifying CRPC tumors