The perinephric space is a cone-shaped retroperitoneal compartment containing the kidney, adrenal gland, perinephric fat, fibrous bridging septa, and a rich network of perirenal vessel and lymphatics. Perinephric space pathology may originate from within or outside the confines of the perirenal fascia. Most intrinsic perinephric space disease arises from the kidney or adrenal gland, and secondarily involves the perinephric space. Disease originating outside the cone of renal fascia may spread to the perinephric space via lymphatics (i.e., metastatic spread) or by directly transgressing perirenal fascial planes (e.g., invasive tumor or infections). Additionally, infiltrating soft tissue or rapidly accumulating retroperitoneal fluid may travel into or out of the perinephric space via perinephric bridging septa and renal fascia. In this article, we review the normal anatomy of the perinephric space and renal fascia, emphasizing the significance of retroperitoneal interfascial planes and perinephric bridging septa as a potential conduit for retroperitoneal disease spread. This review of normal anatomy and pathways of disease spread serves as background for a discussion of a variety of specific pathologic conditions that may involve the perinephric space and retroperitoneal fascia, including pancreatitis, retroperitoneal hematoma, urinoma, metastatic disease, and perirenal varices.