Sensors are a sample contacting technology, and when exposed to biological matrices tend to suffer from the problem of poor biocompatibility and surface fouling. The effects are evidenced by time dependent signal drift (particularly for those devices which are implanted intravascularly). Practical methods to reduce such effects require an understanding of the interface between the electrode and its environment prior to assessment of the potential areas for improvement. Current procedures employed to overcome the observed losses in electrode sensitivity (following exposure to whole blood) include surface modification of the outer diffusion limiting membrane (via variation in film porosity) or even biomimicry of the fluid cell membrane. At amperometric electrodes incorporation of additional inner perm-selective membranes has achieved a reduction in electrode passivation from undesirable surface active compounds as has the use of low polarisation potentials. Other studies have attempted to induce an aqueous barrier between the matrix and the electrode tip which physically prevents passage of cellular components from the sensor surface. Careful choice of the system and materials will ultimately lead to biocompatible non-fouling devices capable of functioning in an array of bio-environments suitable for clinical monitoring of the critically ill patient.