Objectives: To review literature regarding alefacept, a biologic therapy for psoriasis. Methods: A PubMed search using the term alefacept was done through December of 2006 and articles reviewed. Abstracts concerning alefacept presented at the meeting of the Annual meeting of the American Academy of Dermatology in 2004, 2005 and 2006 were reviewed. Attention was paid to alefacept's safety profile, off‐label uses, and potential as part of combination therapy for psoriasis. Results: Alefacept is a very safe treatment for psoriasis alone or in conjunction with other therapies. It has been used, anecdotally, with some effect in diseases besides psoriasis. Conclusions: The utility of checking CD4 counts while administering alefacept for 12 weeks is unclear. While no side effects have been linked to CD4 counts lower than 250/cc³, due to the fact that in clinical trials alefacept was discontinued when the CD4 count was lower than 250/cc³, the effect of administration of alefacept to patients with low CD4 counts is unknown. Alefacept appears to be the safest biologic therapy for the treatment of psoriasis, safety that has been borne out in patients who have received as many as nine courses of alefacept. Intramuscular alefacept's consistent ability to decrease the psoriasis area and severity index (PASI) scores in psoriatic patients is not as great as phototherapy, cyclosporine, methotrexate or tumor necrosis factor alpha blockers. Repeated courses of alefacept are best used in patients who have previously responded to the medication, so that patients who have found alefacept useful when grouped achieve higher and more consistent improvements of PASI scores with each successive course of alefacept. A test that would identify likely responders would greatly increase the utility of the medication. While reports assessing the combination of alefacept and narrow band ultraviolet B phototherapy have only studied small numbers of patients (∼60), the combination of phototherapy and alefacept appears synergistic and extremely effective with studied patients achieving PASI 75 in more than 75% of cases and thus merits further study. Combinations of alefacept with etanercept, acitretin, and methotrexate have been used anecdotally but effectively to treat recalcitrant psoriasis. Reported effective off‐label uses of alefacept include: generalized lichen planus, alopecia areata, steroid‐resistant or steroid‐dependent acute graft‐versus‐host disease, scleroderma, nail psoriasis, and palmoplantar psoriasis.