Selective peptide inhibitors of Bfl-1 were identified by screening for sequence variants of the BH3 motif of PUMA, a highly potent binder of Bcl-2 family members. Peptides were designed using computational analysis followed by experimental screening that identified peptides with high affinity for Bfl-1 yet weakened interactions with other anti-apoptotic proteins. The lead peptide inhibitors are >100-fold selective for binding to Bfl-1 binding over other anti-apoptotic proteins of Bcl-2 family. Selectivity towards Bfl-1 was further augmented by modifying the peptide inhibitors with electrophiles to allow for covalent interaction in the binding pocket of Bfl-1. The selectivity of the peptide Bfl-1 inhibitors in a cellular context was confirmed by the relative mitochondrial depolarization or cytochrome-c release after peptide treatment of Bfl-1 dependent cells vs. other anti-apoptotic protein dependent cells.