This chapter presents a comprehensive scheme for automated detection of colorectal polyps in computed tomography colonography (CTC) with particular emphasis on robust learning algorithms that differentiate polyps from non-polyp shapes. The authors’ automated CTC scheme introduces two orientation independent features which encode the shape characteristics that aid in classification of polyps and non-polyps with high accuracy, low false positive rate, and low computations making the scheme suitable for colorectal cancer screening initiatives. Experiments using state-of-the-art machine learning algorithms viz., lazy learning, support vector machines, and naïve Bayes classifiers reveal the robustness of the two features in detecting polyps at 100% sensitivity for polyps with diameter greater than 10 mm while attaining total low false positive rates, respectively, of 3.05, 3.47 and 0.71 per CTC dataset at specificities above 99% when tested on 58 CTC datasets. The results were validated using colonoscopy reports provided by expert radiologists.