Many traditional contraindications to hormone replacement therapy (HRT) are based on the theoretical potential for these hormones to worsen a disease process and are rarely based on supporting data. This review addresses the available data and lack of data that make the prescription of HRT difficult in a variety of common morbidities. In each circumstance, it is assumed that conservative evidence-based therapies have been tried and that menopausal symptoms remain debilitating and are reducing quality of life. Tailoring of the product, dose, route and regimen may avoid some of the theoretical risks of HRT in particular women or conditions and guidelines are given for each co-morbidity. Specifically, it is discussed that tailored HRT may be used without strong evidence of a deleterious effect after ovarian cancer, endometrial cancer, most other gynecological cancers, bowel cancer, melanoma, a family history of breast cancer, benign breast disease, in carriers of BRACA mutations, after breast cancer if adjuvant therapy is not being used, past thromboembolism, varicose veins, fibroids and past endometriosis. Relative contraindications are existing cardiovascular and cerebrovascular disease and breast cancer being treated with adjuvant therapies. Consultation with other carers and written consent are recommended in all these difficult circumstances, but no condition is an absolute contraindication to HRT if potential risk is understood, if HRT is effective in symptom control and if quality of remaining life is paramount.