The treatment of chronic inflammatory conditions often involves a difficult balance between the benefits of disease modification and the risks attendant with the use of disease-modifying agents. Methotrexate is a useful and commonly used disease-modifying agent but has a particularly notable reputation for causing morbidity and mortality. We explore ways in which the safety of methotrexate prescribing may be improved. There has been considerable debate as to the whether some of the side-effects can be mitigated by co-prescription of folate with methotrexate. Whereas no definitive conclusion can yet be reached, evidence suggests that the improvement in side-effect profile is limited to fewer elevations of liver enzymes, but that this may be at the expense of decreased methotrexate efficacy. The question remains as to whether the improved tolerability more than compensates for the decreased efficacy or whether folic acid should be used in a more circumspect way. However, a very specific danger arises from the fact that methotrexate is prescribed once weekly for inflammatory conditions, leading to errors at both the prescription and patient level. We highlight simple ways of improving safety to decrease such errors.