Cyclosporine, the prototype calcineurin inhibitor, transformed immunosuppressant regimens and practices post-organ transplantation. Therapeutic uses of cyclosporine branched out to include management of different autoimmune disorders. However, multiple additional effects posed significant clinical challenges in face of the prolonged nature of cyclosporine use. Significantly, cyclosporine produced nephrotoxic, cardiotoxic and neurotoxic effects in addition to alteration of hemodynamic function. These adverse effects are shared with other drug groups further complicating the therapeutic situation to include potential exacerbation in case of drug interactions. The potential for detrimental outcomes increases with commonly used drugs such as non-steroidal anti-inflammatory drugs also notorious for their deleterious renal and cardiovascular effects. Herein, we review the available experimental and clinical evidence describing the mechanisms and the outcomes of interactions between the two drug classes. Special attention is given to the divergent toxic effects of co-administration of cyclosporine with selective vs. non-selective cyclooxygenase inhibiting non-steroidal drugs.