Alefacept is the first biologic therapy approved by the United States Food and Drug Administration for the management of patients with moderate-to-severe chronic plaque psoriasis. Alefacept is a fully human fusion protein with a dual mechanism of action inhibiting T-cell activation as well as selectively reducing memory T cells. More than 2000 psoriasis patients have been treated with alefacept in clinical trials. These studies reveal an excellent clinical response, with 33% of patients achieving a Psoriasis Area Severity Index (PASI) score of 75 and 57% of patients achieving a PASI 50 after one course of alefacept. Patients achieving both PASI 75 and PASI 50 have significant improvements in their quality of life. The best responders can have long remissions, and there is a tendency toward continued improvement with subsequent courses of alefacept. The safety profile over the short and intermediate term is excellent. Preliminary data regarding alternate dosing regimens, transitioning patients from conventional systemics to alefacept, and combining alefacept with ultraviolet light therapy will be highlighted. We also will discuss our practical approach to patient selection, CD4 monitoring, management of infections while on alefacept, as well as decisions regarding retreatment and combination therapy.