Introduction: Pulmonary embolism (PE) is a diagnostic challenge, since it shares symptoms with other conditions. Missed diagnosis puts patients at a risk of a potentially fatal outcome, while false positive results leave them at risk of side effects (bleeding) from unnecessary treatment. Diagnosis involves a multi-step pathway consisting of clinical prediction rules (CPRs), laboratory testing, and diagnostic imaging, but the best strategy in the Canadian context is unclear. Methods: We carried out a systematic review of the diagnostic accuracy, clinical utility, and safety of diagnostic pathways, CPRs, and diagnostic imaging for the diagnosis of PE. Clinical prediction rules were studied by an overview of systematic reviews, and pathways and diagnostic imaging by a primary systematic review. Where feasible, a diagnostic test meta-analysis was conducted, with statistical adjustment for the use of variable and imperfect reference standards across studies. Results: The Wells CPR rule showed greater specificity than the Geneva, but the relative sensitivities were undetermined. Application of a CPR followed by with D-dimer laboratory testing can safely rule out PE. In diagnostic test accuracy meta-analysis, computed tomography (CT) (sensitivity 0.973, 95% CrI 0.921 to 1.00) and ventilation/perfusion single-photon emission CT (VQ-SPECT) (sensitivity 0.974, 95% CrI 0.898 to 1.00) had the highest sensitivity) and CT the highest specificity (0.987, 95% CrI 0.958 to 1.00). VQ and VQ-SPECT had a higher proportion of indeterminate studies, while VQ and VQ-SPECT involved lower radiation exposure than CT. Conclusion: CPR and D-dimer testing can be used to avoid unnecessary imaging. CT is the most accurate single modality, but radiation risk must be assessed. These findings, in conjunction with a recent health technology assessment, may help to inform clinical practice and guidelines.