Abstract: Histotripsy therapy systems and methods configured for the treatment of tissue are provided, which may include any number of features. Systems and methods for registering a coordinate system of a cone-beam computed tomography (CT) imaging device and a robotic histotripsy system are also provided, including robotically driving a phantom connected to a robotic arm to an imaging location, importing cone-beam CT images captured by a cone-beam CT imaging device of the phantom, displaying an image from the imported cone-beam CT images of the phantom, wherein the displayed image depicts at least one marker in the phantom, assessing a number and orientation of the at least one marker in the imported cone-beam CT images compared to a known number and orientation of the at least one marker in the phantom, and registering a coordinate system of the cone-beam CT imaging device to a coordinate system of the histotripsy system.