MRI techniques are widely and successfully applied in medicine and biophysics because MRI provides good contrast between different soft tissues without ionizing radiation. MRI protocols are optimized in four aspects: imaging parameters, k-space strategies, RF system calibration and contrast inhomogeneity correction. The signal intensities of normal and disease tissues are simulated, for example, using Bloch equations for an imaging sequence with tissue MR parameters. The relationships between imaging parameters and tissue contrasts are calculated using the numerically simulated signal intensities. The optimal imaging parameters and/or k-space strategies are determined to maximize image contrast and minimize artifacts with acceptable spatial-temporal resolution based on characterization of the imaging hardware. The RF system is optionally calibrated to improve the accuracy of the imaging parameters and reduce inter-scanner variability. Additionally, contrast-to-noise inhomogeneity caused by transmit field and receive sensitivity is optionally corrected by optimal flip angle and measured receiver sensitivity.