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This chapter describes important changes in the clinical practice and pathological interpretation of prostate cancer (PCa) that stratify PCa into insignificant and significant disease to allow for better patient management and treatment decisions.Among the most important changes over the last half a decade has been the change in PCa grading. A new grading system has been developed that is more patient-centric with more accurate stratification according to risk of disease progression. An additional advance is the recent recommendation to report percentage of pattern 4 in Gleason score 7 cancer that may help identify a subset of these men who have relatively insignificant prostate cancer. The definition of significant PCa at prostatectomy has also been extended from a dichotomized classification into a more tiered nuanced approach. Factors involved in classification of significant cancer at prostatectomy include grade, stage along with classification of extraprostatic extension into focal and nonfocal, and tumor volume. Of these variables, tumor volume appears to be least critical as an independent variable. Promising genetic discoveries may also help predict significant cancer, especially in the small subset of lower-grade cancers.Significant PCa is a spectrum of findings bearing different clinical significance with some nuanced definitions at biopsy and prostatectomy.