Newer immunosuppressive strategies have resulted in a marked reduction in graft rejection after transplantation, with the price being an increase of infectious complications, such as BK-related nephropathy. The targeting of new immunosuppressive pathways, such as interleukin-2–mammalian target of rapamycin inhibition, may have unexpected consequences for the immune response. Cell-depleting agents have long-lasting effects on cellular recovery and function, with the activation of latent viral infections and late viral and fungal infections. The multitude of different induction and maintenance protocols renders the detection of small increases of often rare infections very difficult. At the same time, preemptive and prophylactic strategies have gained widespread acceptance and may further offset small changes in infection rates. Other factors related to an increase or shift of infections may be of equal importance, such as increased use of marginal donors, older age at transplantation, or more patients receiving a second transplant. Not all the changes observed result in an increased immunosuppression. Steroid- and calcineurin inhibitor-sparing protocols may have a beneficial impact on infectious complications. Antimycotic or antiviral activity has been described for specific immunosuppressive agents, although the in vivo effect of these activities is uncertain. The possible role of specific drugs in the occurrence of infections is discussed, with emphasis on the antibodies and fusion proteins. The unequivocal attribution of a given infection to a specific drug is often impossible, as the risk of infection is dependent on the entirety of immunosuppression and the epidemiological pressure (‘net immunosuppression’). It is important to remain vigilant for unexpected infections, not only in the context of clinical studies with selected patients, but also in the routine follow-up of our transplant patients.