Urokinase plasminogen activator receptor (uPAR) is a key component in proteolysis and extracellular matrix degradation during cancer invasion and metastasis. uPAR overexpression is an important biomarker for aggressiveness in several solid tumors and provides independent clinical information. A recent major breakthrough was obtained with human translation of uPAR PET using ⁶⁸Ga-NOTA-AE105. Clinical results are encouraging and several large-scale clinical trials are now ongoing. This review focuses on uPAR PET with ⁶⁸Ga-NOTA-AE105 as a new broadly applicable diagnostic and prognostic imaging biomarker in cancer.