A management algorithm for large renal cyst in autosomal dominant polycystic kidney disease (ADPKD) is lacking despite the potential to cause widespread medical and surgical complications. We report the case of a 37-year-old gentleman with ADPKD and large (>5 cm diameter) cysts who suffered sudden death due to autopsy-proven inferior vena cava and pulmonary arterial thrombosis. In this article, we discuss the possible pathophysiological factors at play in this catostrophic complication of ADPKD. We also review available literature to establish the prevalence of such a complication and also establish current thoughts and opinions as to the optimal management strategy for giant cysts in the context of ADPKD.