Since the seventies, positron emission tomography (PET) has become an invaluable medical molecular imaging modality with an unprecedented sensitivity at the picomolar level, especially for cancer diagnosis and the monitoring of its response to therapy. More recently, its combination with x-ray computed tomography (CT) or magnetic resonance (MR) has added high precision anatomic information in fused PET/CT and PET/MR images, thus compensating for the modest intrinsic spatial resolution of PET. Nevertheless, a number of medical challenges call for further improvements in PET sensitivity. These concern in particular new treatment opportunities in the context personalized (also called precision) medicine, such as the need to dynamically track a small number of cells in cancer immunotherapy or stem cells for tissue repair procedures. A better signal-to-noise ratio (SNR) in the image would allow detecting smaller size tumours together with a better staging of the patients, thus increasing the chances of putting cancer in complete remission. Moreover, there is an increasing demand for reducing the radioactive doses injected to the patients without impairing image quality. There are three ways to improve PET scanner sensitivity: improving detector efficiency, increasing geometrical acceptance of the imaging device and pushing the timing performance of the detectors. Currently, some pre-localization of the electron-positron annihilation along a line-of-response (LOR) given by the detection of a pair of annihilation photons is provided by the detection of the time difference between the two photons, also known as the time-of-flight (TOF) difference of the photons, whose accuracy is given by the coincidence time resolution (CTR). A CTR of about 10 picoseconds FWHM will ultimately allow to obtain a direct 3D volume representation of the activity distribution of a positron emitting radiopharmaceutical, at the millimetre level, thus introducing a quantum leap in PET imaging and quantification and fostering more frequent use of ¹¹ C radiopharmaceuticals. The present roadmap article toward the advent of 10 ps TOF-PET addresses the status and current/future challenges along the development of TOF-PET with the objective to reach this mythic 10 ps frontier that will open the door to real-time volume imaging virtually without tomographic inversion. The medical impact and prospects to achieve this technological revolution from the detection and image reconstruction point-of-views, together with a few perspectives beyond the TOF-PET application are discussed.