PET imaging can be deployed to enhance research on human biological or pathological functions, gene expression/therapy for cancer, drug-development research and improving clinical diagnosis by localizing tumors, thus improving the accuracy of staging and treatment planning. Time-of-flight (TOF) PET technology has the potential to increase the effective PET detection sensitivity by multiple times, depending on the TOF timing resolution. Current clinical PET with L(Y)SO scintillation crystals reported TOF resolution of 650-1200 ps that potentially increase the effective PET sensitivity by 2-3 times. Our preliminary study shows that a TOF timing resolution of 300-350 ps is achievable, thereby potentially enhancing the effective PET sensitivity by 4-6 times, so wholebody can be scanned in 5 minutes instead of 30 minutes and a brain/heart scan in 1 minute. Using the photomultiplier-quadrant-sharing (PQS) detector design we have successfully developed human PET detectors with 2.4-mm spatial resolution while reducing photomultiplier (PMT) cost by 75% concurrently, compared to the 4-6.5 mm resolution in present clinical PET using 4 times more PMT. PMT is a major cost in PET. We also found that the internal structure of our detector provides more light-output than the current detector designs, which could potentially improve TOF time resolution from the current 650-1200 ps to 320-350 ps, thereby potentially improving PET's effective detection sensitivity by 4-6 times. Secondly, we conceived a simple electronic method to make a phoswich detector concept work in a large system such as PET, which may improve resolution of clinical PET to 1.6-2 mm, or to decode the depth-of-interaction in 2-layer detectors. Due to the potentially better TOF time resolution of detectors to be developed by our group or others in the future, better and faster TOF detector electronics are needed to fully realize the future TOF timing resolution of these better detectors; Hence, we also propose to develop better TOF-PET electronics. We will also adopt the detector production technology developed to build a TOF-PET testing platform, using the technology developed in this project, to quantify the effectiveness of TOF imaging for lesion detection as a function of patient sizes, TOF resolution, spatial resolution and different lesion-to-tissue contrast ratios. The long-term goals are (a) to develop lower-cost, higher-resolution, higher-sensitivity TOF PET or TOF- PET-CT for earlier cancer detection and more accurate cancer staging, (b) to shorten wholebody scan time from 30 minutes to 5 minutes to improve patient comfort, to reduce patient-motion artifacts in PET images, and to reduce misregistration between PET and CT images caused by patient motion, (c) to lower the high cost of TOF-PET and to significantly increase patient throughput to reduce the high cost of clinical PET scans for better affordability to patients and our society to alleviate the ever increasing cost of health care and high-tech medicine, and (d) ultrahigh resolution and 1-minute scan of brain or other areas open new windows seeing brain function, psychological and neuronal response, dynamic cancer tracers and multi-tracer cancer imaging.