Protein-protein interactions (PPIs) play crucial roles in cell proliferation, differentiation, and apoptosis. Apoptosis is a highly regulated process of cell death and its dysregulation can lead to a multitude of different pathophysiologies, such as cancer. In particular, the overexpression of pro-life Bcl-2 proteins, such as Bcl-2, Bfl-1, and Mcl-1, has been linked to cancer progression and tumorigenesis, as well as chemoresistance to a number of different chemotherapeutics. The binding counterparts of these proteins, pro-death Bcl-2 proteins such as Bim, and p53 transactivation domain (TAD), exert their effects through α-helix mediated PPIs with key residues i, i+ 3/4, and i+ 7 oriented on one side of the helix. In addition, HDM2, the E3 ubiquitin protein ligase responsible for the degradation of p53, is upregulated in numerous cancers, and given the similarities of the recognition profiles of Bim-BH3 and p53TAD, we have designed α-helix mimetic inhibitors that target Mcl-1 and HDM2. The first generation of compounds included various heterocyclic scaffolds, including isoxazoles, pyrazoles, and thiazoles, that project functional groups in a similar manner to the native α-helices. In addition, bicyclic scaffolds have been utilized in Mcl-1 selective inhibition. Therefore, we developed a second generation of compounds of isoxazoles, pyrazoles, and functionalized indoles to further explore the binding interface of Mcl-1. The recent resurgence of covalent inhibition and targeted protein degradation has led to the development of successful Bcl-2 family inhibitors. We have designed two tris-aryl α-helix mimetic scaffolds targeting the Bfl-1 pro-life protein. A unique surface-accessible cysteine within the BH3 domain allows for the development of reversible and irreversible small molecule covalent inhibitors. In addition, we have also designed a venetoclax-based PROTAC targeting Bcl-2.