Several model studies have shown potential clinical advantages with charged particles (protons and light ions) compared with 3D-conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) in many disease sites. The newly developed intensity-modulated proton therapy (IMPT) often yields superior dose distributions to photon IMRT, with the added advantage of a significant reduction in the volume of healthy normal tissues exposed to low-to-medium doses. Initially, the major emphasis in clinical research for proton and light ion therapy was dose escalation for inherently radioresistant tumors, or for lesions adjacent to critical normal structures that constrained the dose that could be safely delivered with conventional x-ray therapy. Since the advent of IMRT the interest in particle therapy has gradually shifted toward protocols aimed at morbidity reduction. Lately the emphasis has mostly been placed on the potential for reduced risk of radiation-induced carcinogenesis with protons. Compared with 3D-CRT, a 2-fold increase has been theoretically estimated with the use of IMRT due to the larger integral volumes. In the pediatric setting, due to a higher inherent susceptibility of tissues, the risk could be significant, and the benefits of protons have been strongly emphasized in the literature. There is a significant expansion of particle therapy facilities around the world. Increasing public awareness of the potential benefits of particle therapy and wider accessibility for patients require that treating physicians stay abreast of the clinical indications of this radiotherapy modality. The article reviews the available literature for various disease sites in which particle therapy has traditionally been considered to offer clinical advantages and to highlight current lines of clinical research. The issue of radiation-induced second malignancies is examined in the light of the controversial epidemiological evidence available. The cost-effectiveness of particle therapy is also discussed.