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Blossom-end rot (BER) is a physiological disorder causing severe losses in tomato crops. Despite its economic importance and the large collection of studies concerning its onset, BER occurrence is still poorly understood, making its prediction and prevention very difficult. Currently, two theories are accredited to explain the BER onset: the first one identifies a reduced root uptake and an aberrant regulation of cellular partitioning of calcium as the major physiopathy agent, while the second one hypothesizes a primary role to abiotic stresses, as they induce reactive oxygen species (ROS) production in the plant, leading to membranes disintegration and loss of cell turgor. To date, there are no unequivocal proofs that allow us to definitively go beyond one of the two hypotheses. Rather, a multitude of genetic, physiological and environmental factors form a complex network of interactions and synergies contributing to BER occurrence. This is why the "multi-disciplinary approach" is maybe the most appropriate one to understand this physiopathy and to develop new and effective BER-contrasting tools with genetic and agronomic methods. This review adopts this kind of approach to investigate the causes of BER and to describe the practices preventing its occurrence, possibly providing the most complete compendium about this disorder to date.