Biological therapeutics are widely used in chronic inflammatory and malignant disease. The underlying mechanisms of treatment failure for these drugs are poorly understood. Resistance to these biological agents and the further subdivision into intrinsic and acquired resistance are not clearly defined. In this review, we explore the current understanding of the mechanisms of action of several biological agents as well as the complex biological processes that underlie resistance. A better understanding of why biologicals fail might help to improve their single or combinational use and will ultimately help to alleviate disease burden more efficiently.