Biocatalysis is an excellent alternative to classical chemical catalysis offering environmentally benign manufacturing, sustainable development and green chemistry. Understanding enzyme properties at an atomic level is the major advantage offered by computational techniques and the only route for rational engineering of enzyme properties. This work describes specifically developed state of the art methodologies that deal with enzyme reaction promiscuity and substrate promiscuity phenomena. An innovative tool for in silico enzyme evolution and screening has also been developed and its assembly from scratch and validation are thoroughly described. The existing drawbacks of industrial application of enzymes need to be overcome by a combined effort of scientists in which computational chemists and biologists have much to contribute.