Timely follow-up for positive cancer screening results remains suboptimal, and the evidence base to inform decisions on optimizing the timeliness of diagnostic testing is unclear. This systematic review evaluated published studies regarding time to follow-up after a positive screening for breast, cervical, colorectal, and lung cancers. The quality of available evidence was very low or low across cancers, with potential attenuated or reversed associations from confounding by indication in most studies. Overall, evidence suggested that the risk for poorer cancer outcomes rises with longer wait times that vary within and across cancer types, which supports performing diagnostic testing as soon as feasible after the positive result, but evidence for specific time targets is limited. Within these limitations, we provide our opinion on cancer-specific recommendations for times to follow-up and how existing guidelines relate to the current evidence. Thresholds set should consider patient worry, potential for loss to follow-up with prolonged wait times, and available resources. Research is needed to better guide the timeliness of diagnostic follow-up, including considerations for patient preferences and existing barriers, while addressing methodological weaknesses. Research is also needed to identify effective interventions for reducing wait times for diagnostic testing, particularly in underserved or low-resource settings. CA Cancer J Clin 2018;68:199-216. © 2018 American Cancer Society.