Synthetic biology has made it possible to rewire natural cellular responses to treat disease, notably demonstrated by chimeric antigen receptor (CAR) T cells as cancer immunotherapy. Building on the success of T‐cell activation using synthetic receptors, the field is now investigating how induction of noncanonical signalling pathways and sophisticated synthetic gene circuitry can enhance the antitumour phenotype of engineered T cells. This commentary explores two recently published studies that provide proof of concept for how new technologies achieve this. The first demonstrated that non‐naturally occurring combinations of signalling motifs derived from various immune receptors and arranged as a CAR drove unique signal transduction pathways in T cells and improved their tumour killing ability. Here, machine learning complemented the screening process and successfully predicted CAR T‐cell phenotype dependent on signalling motif choice. The second explored how synthetic zinc fingers can be engineered into controllable transcriptional regulators, where their activity was dependent on the presence or absence of FDA‐approved small‐molecule drugs. These studies are pivotal in expanding the design choices available for gene circuits of the future and highlight how a single cellular therapy could respond to multiple environmental cues including target cell antigen expression, the tumour microenvironment composition and small molecule drugs.