In the last four decades, biologics have been recognized as an important class of drugs for the treatment of debilitating autoimmune, metabolic, neurological diseases, and cancer. We will review the evolution of biologics, current status, and considerations in their development as drugs. During the course of this scientific breakthroughs, technical and manufacturability challenges combined with commercialization and regulatory considerations for product approval have led to improved design and development course of the biologic drugs, which now incorporate product’s end goals for high quality, optimal activity, improved safety, and delivery for a given indication at the very early phase of the drug discovery and design. This chapter will discuss how engineering of formats has enabled optimization of biologics to maximize their effectiveness and minimize potential safety issues. We will also briefly describe potential pharmacological and safety issues observed with experimental drugs such as (i) short half life, (ii) development of neutralizing anti-drug antibodies, (iii) preclinical false alarms and/or redundant target biology and (iv) undesired safety concerns. Finally, we will discuss next generation therapeutics that uses antibody and its derivatives to develop novel classes of drugs (e.g., bispecifics, bifunctional, T cell engagers, ADCs, etc.).