Unusual lesions of the breast can present a diagnostic challenge. These lesions include systemic diseases, benign tumors, and primary and metastatic malignancies. Lymphadenopathy is the most common mammographic finding associated with collagen vascular disease. Wegener granulomatosis may manifest as an irregular, high-density mass simulating breast cancer. Diabetic fibrous mastopathy manifests at mammography as very dense breast tissue and at ultrasonography (US) as an irregular, hypoechoic mass with striking posterior acoustic shadowing simulating malignancy. Fibromatosis simulates malignancy at mammography as an irregularly shaped, uncalcified, high-density mass and at US as an irregular, hypoechoic mass with posterior acoustic shadowing. At US, granular cell tumor may manifest as a solid, poorly marginated mass with marked posterior acoustic shadowing or may appear more benign. At mammography, hamartomas are typically well-circumscribed, round to oval masses with a thin, radiopaque pseudocapsule; at US, they manifest as a sharply defined, heterogeneous oval mass or as normal glandular tissue. Phyllodes tumor manifests at mammography as a large, well-circumscribed oval or lobulated mass; at US, it usually manifests as an inhomogeneous, solid-appearing mass. At mammography, primary breast lymphoma manifests as a relatively circumscribed mass or a solitary, indistinctly marginated, uncalcified mass. Metastatic lesions may manifest mammographically as single or multiple masses or as diffuse skin thickening; at US, they tend to have circumscribed margins with low-level internal echoes. Radiologists should be familiar with the characteristic mammographic appearances of these lesions and should consider benign and systemic causes in the differential diagnosis when malignant-appearing findings are encountered.