Primary malignancies of the liver and the gastrointestinal tract constitute one of the main health problems worldwide. Together, these types of tumour are the first cause of death due to cancer, followed by lung and breast cancer respectively. One important limitation in the treatment of these tumours is that, with a few exceptions, they exhibit marked resistance to currently available drugs. Moreover, most of them develop chemoresistance during treatment. The mechanisms responsible for drug refractoriness in gastrointestinal tumours include a reduction in drug uptake; enhanced drug export; intracellular inactivation of the effective agent; alteration of the molecular target; an increase in the activity of the target route to be inhibited or the appearance or stimulation of alternative routes; enhanced repair of drug-induced modifications in the target molecules, and the activation/inhibition of intracellular signalling pathways, which leads to a negative balance between the apoptosis/survival of tumour cells. A better understanding of these mechanisms is needed in order to develop accurate tests to predict the lack of response to chemotherapy and novel approaches aimed at overcoming resistance to anticancer agents. The purpose of the present review is to offer an updated overview of the molecular mechanisms of resistance to cytostatic drugs in the most frequent types of primary malignant tumour affecting the liver and gastrointestinal tract.