Although medical literature and differential diagnoses discussions tend to be organ specific, systemic diseases more commonly manifest with multi-organ involvement. Detection of dual organ involvement combined with clinical history narrows the differential to provide a more specific diagnosis. Two organs closely linked are the liver and the spleen. Many processes affect both of these organs through their common denominator, the reticuloendothelial system (RES). This pictorial essay reviews the wide spectrum of benign and malignant pathologies to be considered when computed tomography (CT) demonstrates concurrent focal disease in the liver and spleen.