Background For patients with suspicious lung lesions found on chest x-ray or CT, endo/trans- bronchial biopsy of the lung is the preferred method for obtaining a diagnosis. With the addition of new screening programs, a higher number of patients will require diagnostic biopsy which will prove even more challenging due to the small size of lesions found with screening. There are many endobronchial tools available on the market today and a wide range of new tools under investigation to improve diagnostic yield. However, there is little information available about the optimal tool size required to reach the majority of lesions, especially peripheral ones. In this manuscript we investigate the percentage of lesions that can be reached for various diameter tools if the tools remain inside the airways (i.e. endobronchial biopsy) and the distance a tool must travel “off-road” (or outside of the airways) to reach all lesions. Methods and findings To further understand the distribution of lung lesions with respect to airway sizes and distances from the airways, six 3D models of the lung were generated. The airways were modeled at two different respiratory phases (inspiration and expiration). Three sets of 1,000 lesions were randomly distributed throughout the lung for each respiratory phase. The simulations showed that the percentage of reachable lesions decreases with increasing tool diameter and decreasing lesion diameter. A 1mm diameter tool will reach <25% of 1cm lesions if it remains inside the airways. To reach all 1cm lesions this 1mm tool would have to navigate through the parenchyma up to 8.5mm. CT scans of 21 patient lesions confirm these results reasonably well. Conclusions The smaller the tool diameter the more likely it will be able to reach a lung lesion, whether it be for diagnostic biopsy, ablation, or resection. However, even a 1mm tool is not small enough to reach the majority of small (1-2cm) lesions. Therefore, it is necessary for endobronchial tools to be able to navigate through the parenchyma to reach the majority of lesions.@en