The third decade of the 21 century marks the beginning of a new era in the treatment of rheumatoid arthritis (RA). Recently, after the introduction in clinical practice of different biologics in the first decade, three different oral synthetic targeted agents (JAK inhibitors) have been licensed for the treatment of RA, in patients who had failed or are intolerant to disease modifying anti-rheumatic drugs (DMARDs). Despite the significant progress that these agents bring to the care of RA patients, the risk of infections is still present and clear, given that their risk for serious infections is at least comparable with that of biologic DMARDs, whereas the incidence of herpes zoster is higher than that of bDMARDs. Here, we review the most recent data regarding the risk for serious and opportunistic infections in RA patients treated with biologics or JAK inhibitors, as well the up-to-date approach for managing and preventing such infections in RA patients.