In this book the fully automatic generation of semantic annotations for medical imaging data by means of medical image segmentation and labeling is addressed. In particular, the focus is on the segmentation of the human brain and related structures from magnetic resonance imaging (MRI) data. Three novel probabilistic methods from the field of database-guided knowledge-based medical image segmentation are presented. Each of the methods is applied to one of three MRI segmentation scenarios: 1) 3-D MRI brain tissue classification and intensity non-uniformity correction, 2) pediatric brain cancer segmentation in multi-spectral 3-D MRI, and 3) 3-D MRI anatomical brain structure segmentation. All the newly developed methods make use of domain knowledge encoded by probabilistic boosting-trees (PBT), which is a recent machine learning technique. For all the methods uniform probabilistic formalisms are presented that group the methods into the broader context of probabilistic modeling for the purpose of image segmentation. It is shown by comparison with other methods from the literature that in all the scenarios the newly developed algorithms in most cases give more accurate results and have a lower computational cost. Evaluation on publicly available benchmarking data sets ensures reliable comparability of the results to those of other current and future methods. One of the methods successfully participated in the ongoing online caudate segmentation challenge (www.cause07.org), where it ranks among the top five methods for this particular segmentation scenario.