In response to the need to treat disorders such as Crohn’s disease, rheumatoid arthritis, allergies, and diabetes, the pharmaceutical industry has pursued the development of cytokines as therapeutic agents. Cytokines possess unique characteristics that are distinctly different than small molecule drugs. These hormone-like proteins possess complex structural features, demonstrate unique binding specificities and, in many cases, share overlapping physiological functions. These characteristics make development of cytokine therapeutics a challenge to drug-development scientists. Preclinical development of these molecules is complicated by the challenge of differentiating between toxicity and exaggerated immunopharmacology and understanding and analyzing the impact of antidrug antibody on the pharmacodynamics and pharmacokinetics of the parent compound. Regulatory agencies have recognized these issues and established guidance documents to address the nonclinical development of biological products. Several examples, including the nonclinical development of interleukin (IL)-, IL-5 antagonists, IL-6, IL-10, and IL-18 are reviewed in the context of these issues.