Immune reconstitution inflammatory syndrome (IRIS) must be considered in the differential diagnosis for any patient infected with HIV who has begun ART in the preceding months. Distinguishing between manifestations of IRIS and active infection is of paramount importance and poses a diagnostic challenge to the provider in the acute care setting. Presentations of IRIS are often atypical for the precipitating pathogen, and novel presentations are likely. Of the diseases associated with IRIS, mycobacteria and cryptococcal infections are commonly encountered, as are dermatologic symptoms in general. The most clinically significant complications of IRIS are those involving the central nervous system, lungs, and eye, and in many of these scenarios systemic steroids may be of benefit. Management should rarely include interruption of ART, except possibly in severe, life-threatening complications.