This thesis characterizes the long axial field-of-view (AFOV) PennPET Explorer scanner and studies the benefits for clinical and research applications using both measurements and Monte-Carlo simulations. The significant increase in photon sensitivity from extending the standard AFOV of a PET scanner by 3-6 times to 70-140 cm may allow for fast, low-dose imaging and more accurate quantification using a wide variety of radiotracers. Results of performance characterization, including sensitivity, count rate, spatial resolution, and lesion contrast, showed good correspondence across simulated and measured data, indicating an accurate model of the PennPET Explorer. A key clinical application, lesion detection, was studied with small lesions in both uniform and complex background distributions. Results showed that good lesion detectability and localization was achieved in the human subject for 30-60 s scan durations for the PennPET Explorer, compared to a 1.5-3 min scan on standard AFOV scanners. Dynamic imaging, often required for research applications, was studied using both simulated and measured datasets to quantify the accuracy and precision of key biologic parameters as a function of injected radioactive dose. Results showed that the dose can be lowered from 5-15 mCi, typical with a standard AFOV PET scanner, to 1-2 mCi with our long AFOV scanner while still maintaining accuracy and precision of key biologic parameters. These results were then used to design a dual tracer imaging study to sequentially image two radiotracers, labeled with the same radioisotope, to study complementary mechanisms of metabolism. Preliminary results indicate that a low, 3 mCi dose with the first tracer, imaged for an abbreviated 30 min, and followed by a 15 mCi injection of a second tracer resulted in time-activity curves (TACs) with low noise, and can be used to further optimize this new protocol. Combined, these results offer a quantitative framework for both static and dynamic imaging on the PennPET Explorer and can be applied to develop new clinical and research applications to leverage the enormous potential of long AFOV PET scanners.