In this review, we summarize the false-positive and false-negative results of standard 18F-FDG-PET/CT in characterizing musculoskeletal lesions and discussed the added value and limitations of dual-time point imaging (DTPI) and delayed imaging in differentiating malignant from benign musculoskeletal lesions, based on review of the peer-reviewed literature. The quantitative and semiquantitative parameters adopted for DTPI are standardized uptake value (mainly maximum standardized uptake value [SUVmax]) and retention index (RI), calculated as RI (%) = 100% × (SUV [maxD-Delayed] - SUV [maxE-Early])/SUV [maxE-Early], although the criteria and cutoff for diagnosing malignancy in studies have varied considerably. Also, there has been considerable heterogeneity in protocol (time point of delayed imaging), interpretation, and results in dual-time point (DTP) 18F-FDG-PET for differentiating malignant from benign musculoskeletal lesions in various research studies. The specificity of DTPI is a function of many factors such as the nature of the musculoskeletal lesion or malignancy in question, the prevalence of false-positive etiologies in the patient population, and the cutoff values (either SUVmax or RI) employed to define a malignancy. Despite the apparent conflicting reports on the performance, there have been certain common points of agreement regarding DTPI: (1) DTP PET increases the sensitivity of 18F-FDG-PET/CT due to continued clearance of background activity and increasing 18F-FDG accumulation in malignant lesions, when the same diagnostic criteria (as in the initial standard single-time point imaging) are used. Increased sensitivity for lesion detection can be viewed as a strong point of DTP and delayed-time point imaging. (2) The causes for false positives (such as active infectious or inflammatory lesions and locally aggressive benign tumors) and false negatives (eg, low-grade sarcomas) are the major hurdles accounting for reduced diagnostic value of the technique, with overlap of 18F-FDG uptake patterns between benign and malignant musculoskeletal lesions on DTPI. (3) DTPI, however, could still be potentially useful in increasing the confidence of interpretation such as differentiating malignancy from sites of inactive or chronic inflammation, post-treatment viable residue vs necrosis, and certain other benign lesions. (4) Consideration of diagnostic CT component of PET/CT and the patient's clinical picture can lead to increase in specificity of interpretation in a given case scenario. Further systematic research, adoption of uniform protocol, and interpretation criterion could evolve the specific indications and interpretation criteria of DTPI for improved diagnostic accuracy in musculoskeletal lesions and its clinical applications.