Achieving effectiveness of therapeutic interventions across a diversity of patients continues to be a foremost concern of clinicians and clinical researchers alike. Further, across theoretical orientations and in all treatment modalities, therapy alliance remains a critical component to determine such favorable outcome from therapy. Yet, there remains a scarcity of empirical data testing specific features that most readily facilitate effective collaboration in a multi-cultural therapy relationship. This article reviews the literature on terminology, empirical findings, and features to enhance collaboration in multi-cultural therapy, suggesting guidelines for achieving this goal in therapy with patients (and therapists) of various cultural/racial backgrounds. This is followed by a multi-cultural case study presenting with several co-morbid Axis I disorders, to exemplify the application of these guidelines over the course of therapy.