In principle, intensity-modulated particle (proton and carbon ion) therapy (IMPT) is the most effective way of producing highly conformal radiation dose patterns that offer considerable potential for major improvement in the therapeutic ratio compared to the currently used most advanced modes of radiotherapy. In IMPT, energies and intensities of thousands of individual narrow “beamlets”, comprising particle beams aimed at the target from multiple directions, are optimized using sophisticated computer algorithms to achieve optimum treatment plans. However, the current state of understanding of the fundamental principles underlying IMPT is seriously lacking and may subvert its theoretically enormous potential. The most critical of the limitations include: (1) Particle therapy (especially IMPT) is highly sensitive to uncertainties such as inter- and intra-fractional anatomic changes; and (2) the currently used models for computing radiation dose distributions patterns for planning of treatments are limited in their accuracy. As a consequence, the actual delivered dose distribution may be quite different from the planned one.