The last few years have seen the transfer of two decades of research into Chimeric Antigen Receptors (CARs) into clinical trials. Despite this extensive research, there is still a great deal of debate into the optimal design strategy for these, primarily, anti-cancer entities. The archetypal CAR consists of a single-chain antibody fragment, specific to a tumour-associated antigen, fused to a component of the T-cell receptor complex (typically CD3zeta) which on antigen binding primes the engrafted T-cell for anti-tumour activity. The modular nature of these artificial receptors has enabled researchers to modify aspects of their structure, including the extracellular spacer, transmembrane and cytoplasmic domain, to achieve laboratory defined optimal activity. Despite this there is no consensus on the optimal structure, a problem exacerbated by conflicting results using identical receptors. In this review, we provide a structural overview of CAR development and highlight areas that require further refinement. We also attempt to identify possible reasons for conflicting results in the hope that this information will inspire future rational design strategies for optimal tumour targeting using CARs.