A method of continuous real-time monitoring and positioning of multi-leaf collimators during on and off radiation exposure conditions of radiation therapy to account for target motion relative to a radiation beam is provided. A prediction algorithm estimates future positions of a target relative to the radiation source. Target geometry and orientation are determined relative to the radiation source. Target, treatment plan, and leaf width data, and temporal interpolations of radiation doses are sent to the controller. Coordinates having an origin at an isocenter of the isocentric plane establish initial aperture end positions of the leaves that is provided to the controller, where motors to position the MLC midpoint aperture ends according to the position and target information. Each aperture end intersects a single point of a convolution of the target and the isocenter of the isocentric plane. Radiation source hold-conditions are provided according to predetermined undesirable operational and/or treatment states.