The selectivity of Janus kinase inhibitors (JAKis) is still a matter of debate, as no JAKi is specific for only one Janus kinase (JAK) isoform. Currently approved JAKis in rheumatoid arthritis (RA) all inhibit JAK1, which is an effective therapeutic target in RA. Although selective JAK1 inhibition seems not to decrease drug efficacy, JAKi selectivity may modify the safety profile of this class. Indeed, the balance of benefit and risk of inhibiting JAK2, JAK3 and tyrosine kinase 2 is not certain and should be carefully evaluated in the future.