The present invention relates to small molecule antagonists of Bcl-2 family proteins such as Bcl-2 and/or Bcl-X.sub.L. In particular, the present invention provides non-peptide cell permeable small molecules (e.g., tricyclo-dibenzo-diazocine-dioxides) that bind to a pocket in Bcl-2/Bcl-X.sub.L that block the anti-apoptotic function of these proteins in cancer cells and tumor tissues exhibiting Bcl-2 protein overexpression. In preferred embodiments, the small molecules of the present invention are active at the BH3 binding pocket of Bcl-2 family proteins (e.g., Bcl-2, Bcl-X.sub.L, and Mcl-1). The compositions and methods of the present invention are useful therapeutics for cancerous diseases either alone or in combination with chemotherapeutic or other drugs.