Chemical and biosensors operate as direct sample contact systems; as such, the response of the biomatrix to their presence is as important as their response to the targeted analyte. There needs to be greater research emphasis on the response of biofluids to sensors because of the impact on sensor performance. Mainly, this is the result of deposited biolayers through the adsorption of colloids and proteins, followed by a more complex surface-active system: whole cells. Sensor surface engineering and controlled sample presentation through fluidics are likely to be able to mitigate some of these effects. Overall there needs to be a convergence with rapidly evolving research strategies in biomaterials if sensors are to make the full transition from the laboratory to the real world.