It is the aim of conformal radiotherapy to restrict the high-dose region to the target volume as much as possible, thereby sparing the neighboring healthy tissues. However, to increase the therapeutic range, smaller margins tend to be used. This reduction of safety margins enhances the risk of unsuitable dosage because of mistaken target definition. Central nervous system (CNS) and lung cancers constitute sites that are particularly difficult to irradiate combining a large number of conceptual difficulties, allowing them to be considered as 2 particularly interesting study models. Imaging occupies an increasingly important place in these 2 types of tumors, especially with the development of new radiotherapy techniques. CNS and lung cancers represent an example of clinicopathological correlations. More specifically, CNS cancers represent an excellent model for estimation of new 3-dimensional navigational systems. For lung cancer, there is a combination of ballistic difficulties because of respiratory motion, the number and low tolerance of neighboring organs, and dosimetric difficulties because of the presence of inhomogeneities. This article reviews the main currently accepted criteria of choice justifying the size of gross tumor volume and clinical target volume margins for lung and CNS cancers.