Uterine fibroids are the most common benign tumors in women. Uterine fibroids can cause substantial symptoms including heavy menstrual bleeding, pelvic pressure, and discomfort. MR guided high intensity focused ultrasound (MRgHIFU) uses MRI to monitor thermal ablation of uterine fibroids. It is non-invasive and requires a short recovery time. However, MRgHIFU therapy has several challenges: (1) The long pre-imaging time, which reduces the treatment efficiency and can cause significant patient discomfort. (2) Not all the fibroids are treatable by HIFU therapy. Current studies reported the fibroids with higher signal intensity than muscle and myometrium in T2-weighted image cannot be treated by this method. (3) Evaluation of treatment response requires the use of a MRI contrast based method, which is contra-indicated in patients with dysfunctional kidney. This dissertation focused on strategies to address the aforementioned challenges in MRgHIFU therapy of uterine fibroids via numerical simulations and in vivo animal and human studies. The specific contributions from this dissertation are as follows: (1) The scan time of conventional T2 weighted turbo spin echo (TSE) sequence used to obtain pre-treatment images for MRgHIFU therapy was halved by modifying the TSE sequence with variable refocusing flip angles as well as the application of orthogonal 90°-180° radio-frequency pulses to restrict imaging field-of-view. (2) An intra-voxel incoherent motion (IVIM) based model is proposed in lieu of the current approaches to assess tissue microstructure (diffusion and perfusion) to distinguish treatable and non-treatable fibroids. It is found that with T2-correction, f (blood volume ratio in IVIM) is different for different types of fibroids. (3) Three potential non-contrast based methods to estimate the treatment outcome are proposed. They include the diffusion weighted imaging (DWI), T2 map, and f map, and preliminary evidence is presented. (4) A DWI method to monitor tissue microstructure changes during heating via apparent diffusion coefficient (ADC) based surrogates for diffusion and perfusion is also reported. With further advancement, this work will permit efficient MRgHIFU therapy of uterine fibroids, by reducing pre-treatment imaging time, selection of treatable fibroids based on their microstructure, and monitor treatment outcome during and after MRgHIFU therapy without the need for MRI contrast.