This review provides an overview of Sp1-like proteins and Krüppel-like factors (KLFs), which are highly related zinc-finger proteins crucial for eukaryotic cellular transcriptional machinery. These proteins regulate the expression of genes with GC-rich promoters, influencing various cellular functions such as cell proliferation, apoptosis, differentiation, and neoplastic transformation. The review highlights the evolutionary history, gene organization, and structural features of these proteins, emphasizing their conserved zinc-finger domains and variable amino-terminal regions. It discusses the mechanisms by which Sp1-like/KLF proteins function as activators or repressors, often through interactions with corepressors and coactivators. The review also explores the roles of these proteins in growth-regulatory and developmental processes, their involvement in carcinogenesis, and the potential for developing specific small-molecule antagonists to manipulate their functions. Finally, it outlines future research directions to better understand the regulatory mechanisms and clinical implications of Sp1-like/KLF proteins.This review provides an overview of Sp1-like proteins and Krüppel-like factors (KLFs), which are highly related zinc-finger proteins crucial for eukaryotic cellular transcriptional machinery. These proteins regulate the expression of genes with GC-rich promoters, influencing various cellular functions such as cell proliferation, apoptosis, differentiation, and neoplastic transformation. The review highlights the evolutionary history, gene organization, and structural features of these proteins, emphasizing their conserved zinc-finger domains and variable amino-terminal regions. It discusses the mechanisms by which Sp1-like/KLF proteins function as activators or repressors, often through interactions with corepressors and coactivators. The review also explores the roles of these proteins in growth-regulatory and developmental processes, their involvement in carcinogenesis, and the potential for developing specific small-molecule antagonists to manipulate their functions. Finally, it outlines future research directions to better understand the regulatory mechanisms and clinical implications of Sp1-like/KLF proteins.