Many real-life stains have origins from biological matters including proteins, lipids, and carbohydrates that act as gluing agents binding along with other particulates or microbes to exposed surfaces of automobiles, furniture, and fabrics. Mimicking naturally occurring self-defensive processes, we demonstrate in this work that a solid surface carrying partially exposed enzyme granules protected the surface in situ from contamination by biological stains and fingerprints. Attributed to the activities of enzymes which can be made compatible with a wide range of materials, such anti-contamination and self-cleaning functionalities are highly selective and efficient toward sticky chemicals. This observation promises a new mechanism in developing smart materials with desired anti-microbial, self-reporting, self-cleaning, or self-healing functions. Biotechnol. Bioeng. 2013; 110: 1805–1810. © 2013 Wiley Periodicals, Inc.