Social workers provide services to a variety of clients and are challenged with finding interventions that meet the multifaceted needs of diverse populations. Acceptance and commitment therapy (ACT) is becoming an increasingly popular therapy that offers flexibility and effectiveness in treating challenging cases. The purpose of this review is to provide social work researchers and practitioners with an explanation of the clinical application of ACT. The article provides a systematic review of the existing efficacy of ACT with various health illnesses. The authors gathered articles from multiple databases that investigated ACT as an intervention with psychological and physiological health illnesses and calculated corresponding effect sizes. Effect sizes indicated that ACT is a promising intervention for those with anxiety disorders, depression, psychosis, trichotillomania, epilepsy, chronic skin picking, and diabetes. The research on ACT and its promising applications to help clients with various health illnesses provide social workers with promising alternatives for approaching challenging illnesses. Although the empirical base continues to show promise for ACT, additional research using larger sample sizes and more rigorous designs is needed before more definitive claims can be made about the effectiveness of ACT.