Historically, the use of animal models in drug discovery has been integral to the development of novel therapies. Unfortunately, the translatability of animal model data into the clinical arena continues to be subject to seemingly everlasting debate. While there is an increasing focus to improve translatability of a drug discovery employing in-vitro biologically relevant assays with human tissue, many areas of the complex biology can only be adequately explored in an integrated system represented by animal models. For example, in the areas of inflammation and immunology antigen recognition, presentation and subsequent immune response precipitate a disease phenotype involves multiple cell types that orchestrate a time dependent pathology. Furthermore the exploration of the interplay of a drug's pharmacokinetic (PK) profile with the required pharmacodynamic (PD) response is critical for clinical dose regimen guidance and can only be explored in in vivo animal settings. Thus, research scientist continues to require in vivo models to enhance the probability of successfully advancing novel compounds from the bench to human patients. Central to the PKPD modeling is a deep understanding of the utility and limitations of animal models. In this chapter we make a distinction between pathway biology PD models and disease mechanism models. We provide high level guidance on the use of animals in the context of in vitro pharmacology and PK, focusing on preventing the over-interpretation of the data generated in these preclinical in vivo systems. We discuss practical aspects of experimental design and offer useful considerations for the medicinal chemist and other biomedical scientists on how to effectively build a platform of evidence, which incorporates animal data, to support progression of drug targets. Ethics, relevant species choice, group size, statistics, PD end point and PKPD relationship are also addressed in this chapter.