Applications for acute phase reactants (APRs) in nondomesticated mammals include identifying inflammatory disease, monitoring the course of specific disease processes and recovery during rehabilitation, detecting preclinical or subclinical disease, being used as bioindicators for monitoring population and ecosystem health, and as markers of stress and animal welfare. Serum amyloid A, haptoglobin, C-reactive protein, fibrinogen, albumin, and iron are most commonly measured. The procedure for evaluating an APR in a nondomesticated mammalian species should follow a stepwise approach beginning with an assessment of analytical performance, followed by an evaluation of overlap performance, clinical performance, and impact on patient outcomes and management. The lack of species-specific standards and antibodies for nondomesticated mammals presents a challenge, and more attention needs to be focused on assessing cross-reactivity and ensuring adequate analytical performance of APR assays. Sample selection for the initial evaluation of APRs should consider preanalytical influences and should originate from animals with confirmed inflammatory disease and healthy animals. Reference intervals should be generated according to published guidelines. Further evaluation should focus on assessing the diagnostic utility of APRs in specific disease scenarios relevant to a species. Greater attention should be paid to assay performance and uniformity of methods when using APRs for population and ecosystem surveillance. Veterinary clinical pathologists should work closely with zoo veterinarians and wildlife researchers to optimize the accuracy and utility of APR measurements in these various conservation medicine scenarios.