This article addresses diagnostic challenges involving toxicology cases that are multifactorial in nature, often involving sublethal exposures to multiple toxicants and/or other etiologies that are not toxic. Gold standard diagnostic approaches were developed under the assumption that cases were undoubtedly intoxications, and they still are applicable to those cases. A more integrated diagnostic approach, focusing on the initial problem list, is consistent with how veterinarians diagnose most cases. Livestock ownership attitudes continue to evolve. Ongoing threats to the financial well-being of animal agriculture ultimately will have an impact on the ability of producers to maintain health and performance of livestock.