Biocatalysis has proven to be an essential industrial tool for converting raw material into valuable bio-products. The discovery of new enzymes, the improvement of enzymatic features, and the development of new processes for enzyme production will drive future innovation. For the chemical industry, the use of enzymes presents important benefits, which include higher selectivity, increased sustainability, and a low toxicity. These benefits are translated in cleaner production processes and lower environmental impact. Enzymes derived from extremophiles, or extremozymes, often have extraordinary properties, which include being able to carry out reactions at nonstandard conditions (e.g. high or low temperatures, acidic or alkaline pH, high concentrations of salt or organic solvents, and high pressure) where other enzymes underperform. Working with extremophiles and their native extremozymes is difficult due to the culture conditions required; they have usually low cell yield and low enzyme expression. For these reasons, to achieve industrial production levels, available extremozymes have been overexpressed in suitable heterologous host-vector systems. In this review, we present a road map to find enzymes from extremophiles. We will explore the process from discovering an enzymatic activity in a microbial crude extract through the application of a functional biochemical approach, up to the development of a new enzymatic product.