This application relates to methods for delivering radiation to a positron-emitting target within a subject under continuous PET guidance. Instead of directing radiation at a collinear path along each detected positron line-of-response (LOR), the methods generally include detecting a pattern of LORs that intersect the target. In response to the pattern, radiation may be delivered along paths that are not necessarily collinear to any of the LORs. Methods for further modifying radiation delivery as well as the detected LOR population are also described.