This dissertation focuses on developing imaging informatics algorithms for clinical decision support systems (CDSSs) based on histopathological whole-slide images (WSIs). Currently, histopathological analysis is a common clinical procedure for diagnosing cancer presence, type, and progression. While diagnosing patients using biopsy slides, pathologists manually assess nuclear morphology. However, making decisions manually from a slide with millions of nuclei can be time-consuming and subjective. Researchers have proposed CDSSs that help in decision making but they have limited reproducibility. The development of robust CDSSs for WSIs faces several informatics challenges: (1) Lack of robust segmentation methods for histopathological images, (2) Semantic gap between quantitative information and pathologist’s knowledge, (3) Lack of batch-invariant imaging informatics methods, (4) Lack of knowledge models for capturing informative patterns in large WSIs, and (5) Lack of guidelines for optimizing and validating diagnostic models. I conducted advanced imaging informatics research to overcome these challenges and developed novel methods to extract information from WSIs, to model knowledge embedded in large histopathological datasets, such as The Cancer Genome Atlas (TCGA), and to assist decision making with biological and clinical validation. I validated my methods for two applications: (1) diagnosis of histopathology-based endpoints such as subtype and grade and (2) prediction of clinical endpoints such as metastasis, stage, lymphnode spread, and survival. The statistically emergent feature subsets in the diagnostic models for histopathology-based endpoints were concordant with pathologists’ knowledge.