The identification, referral and specific treatment of midlife patients in primary care who are distressed by mood, anxiety, sleep and stress-related symptoms, with or without clinically confirmed menopausal symptoms, are confounded by many structural issues in the delivery of women’s healthcare. Diagnosis, care delivery, affordability of treatment, time commitment for treatment, treatment specificity for a particular patient’s symptoms and patient receptiveness to diagnosis and treatment all play roles in the successful amelioration of symptoms in this patient population. The value of screening for depression in primary care, the limitations of commonly used screening instruments relative to culture and ethnicity, and which clinical care systems make best use of diagnostic screening programs will be discussed in the context of the midlife woman. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) program illustrates the relatively high rate of unremitted patients, regardless of clinical setting, who are receiving antidepressants. Nonmedication treatment approaches, referred to in the literature as ‘nonsomatic treatments’, for depression, anxiety and stress, include different forms of cognitive-behavioral therapy, interpersonal therapy, structured daily activities, mindfulness therapies, relaxation treatment protocols and exercise. The specificity of these treatments, their mechanisms of action, the motivation and time commitment required of patients, and the availability of trained practitioners to deliver them are reviewed. Midlife women with menopausal symptoms and depression/anxiety comorbidity represent a challenging patient population for whom an individualized treatment plan is often necessary. Treatment for depression comorbid with distressing menopausal symptoms would be facilitated by the implementation of a collaborative care program for depression in the primary care setting.