Based on the authors' experience with more than 40 patients with treatment-refractory schizophrenia, they describe three phases of clozapine treatment. Phase-specific responses of patients and their families during clozapine trials often resemble their reactions during adaptation to chronic schizophrenia. Because the effectiveness of clozapine treatment has been so widely reported, many reactions are based on families' cure and rescue fantasies that resurface and intensify after having previously been worked through. Extreme, paradoxical, and problematic reactions, such as conflicts arising from patients' improved functioning, can threaten the viability of the clozapine trial and must be carefully managed by the therapist. The authors recommend specific treatment approaches for the different phases of the clozapine trial, including family therapy and psychoeducation throughout the trial and an approach based on object relations during the final phase.