Histamine is a biogenic amine that can cause food poisoning in an increasing fraction of the population. Histamine detection and quantification are crucial for evaluating the freshness of food products and informing histamine-sensitive consumers regarding histamine concentration in fermented or processed food products. Several analytical methods exist for quantifying histamine from food samples, most based on chromatographic analysis. This review summarizes the current knowledge of analytical methodologies for detecting and quantifying histamine. We highlight the importance of using timely detection tools for biogenic amines to indicate the degree of freshness or deterioration of food. A multidisciplinary approach based on molecular and enzymatic methods for detecting and quantifying histamine and other biogenic amines is presented, where histamine dehydrogenase and histamine oxidase enzymes from microbial sources stand out as potential molecular tools for histamine detection, and with which rapid, scalable, and user-friendly assay platforms can be used. In addition to typical enzyme technology concerns, the enzymatic detection of histamine faces substrate specificity and substrate inhibition challenges that affect the specific identification of histamine and the detection limit of the enzymatic assay. These challenges can be overcome by enzyme engineering, immobilization, or their simultaneous integration to obtain biocatalysts with increased histamine detection, quantification, or performance.