Diagnosis is the foundation of medicine. Effective treatment cannot begin until an accurate diagnosis has been made. Diagnostic reasoning is a critical aspect of clinical performance. It is vulnerable to a variety of failings, the most prevalent arising through cognitive and affective influences. The impact of diagnostic failure on patient safety does not appear to have been fully recognized. Ideally, all information used in diagnostic reasoning is objective and all thinking is logical and valid, but these conditions are not always met. Two major phenomena that may undermine objectivity and rational thinking are cognitive dispositions to respond (CDRs) and affective dispositions to respond (ADRs) toward the patient. In this report, the determinants and characteristics of the major CDRs and ADRs are reviewed, as are a variety of de-biasing strategies that may mitigate their influence. A retrospective analytical process, the cognitive and affective autopsy, is also described. The purpose of this report is to provide insight into cognitive and affective influences that have resulted in delayed or missed diagnoses.