Security checkpoints are used to keep potentially dangerous items and individuals out of secure areas. Although technological advances can enhance security efficacy through both accuracy and speed, ultimate success or failure is largely determined by human performance. As such, it is necessary to minimize any shortcomings that stem from the limits of human cognitive abilities. Cognitive performance can be influenced by numerous factors, including those imposed by the search task (e.g., the number of prohibited items) and the basic abilities of the searchers themselves (e.g., competency and experience). Here, we review and discuss four specific challenges of the task itself that can negatively affect the accuracy of a security screening: target visibility, an unknown target set, the possible presence of multiple targets, and low target prevalence. For each, we present the challenge faced and the potential significance of the challenge and then offer possible solutions on the basis of the existing literature.