In external beam radiotherapy, modern technologies for dynamic dose delivery and beam conformation provide high selectivity in radiation dose administration to the pathological volume. A comparable accuracy level is needed in the 3-D localization of tumor and organs at risk (OARs), in order to accomplish the planned dose distribution in the reality of each irradiation session. In-room imaging techniques for patient setup verification and tumor targeting may benefit of the combined daily use of optical tracking technologies, supported by techniques for the detection and compensation of organ motion events. Multiple solutions to enhance the use of optical tracking for the on-line correction of target localization uncertainties are described, with specific emphasis on the compensation of setup errors, breathing movements and non-rigid deformations. The final goal is the implementation of customized protocols where appropriate external landmarks, to be tracked in real-time by means of non-invasive optical devices, are selected as a function of inner target localization. The presented methodology features high accuracy in patient setup optimization, also providing a valuable tool for on-line patient surveillance, taking into account both breathing and deformation effects. The methodic application of optical tracking is put forward to represent a reliable and low cost procedure for the reduction of safety margins, once the patient-specific correlation between external landmarks and inner structures has been established. Therefore, the integration of optical tracking with in-room imaging devices is proposed as a way to gain higher confidence in the framework of Image Guided Radiation Therapy (IGRT) treatments.