The Krüppel-like factor (KLF) family of transcription factors regulates diverse biological processes, including proliferation, differentiation, growth, development, survival, and responses to external stress. Seventeen mammalian KLFs have been identified, and numerous studies have described their basic biology and contributions to human diseases. KLFs are critical regulators of physiological systems such as the cardiovascular, digestive, respiratory, hematological, and immune systems, and are involved in disorders like obesity, cardiovascular disease, cancer, and inflammatory conditions. Additionally, KLFs play an important role in reprogramming somatic cells into induced pluripotent stem (iPS) cells and maintaining the pluripotent state of embryonic stem cells. As research on KLF proteins progresses, new functions and associations with disease are likely to be discovered. This review addresses the current understanding of the biochemical, biological, and pathophysiological functions of KLF family members. KLF proteins are conserved among mammals, with many having homologs in various species. Tissue expression varies, with some family members expressed ubiquitously and others in specific tissues. KLF proteins share homology in their carboxyl-terminal zinc finger domains, allowing them to bind GC-rich sites in gene promoters and enhancers. These structural similarities create overlap in their transcriptional targets. KLF proteins have distinct amino-terminal sequences that provide unique regions for interaction with specific binding partners. Phylogenetic analysis of the 17 human KLFs defines evolutionary distances of individual family members. Structural homologies of KLFs correlate with functional similarities, likely due to homologous protein interaction motifs in amino-terminal domains. Based on functional characteristics, KLF proteins can be divided into three distinct groups: Group 1 (KLFs 3, 8, and 12) serve as transcriptional repressors through interaction with CtBP; Group 2 (KLFs 1, 2, 4, 5, 6, and 7) function as transcriptional activators; and Group 3 (KLFs 9, 10, 11, 13, 14, and 16) have repressor activity through interaction with Sin3A. KLFs 15 and 17 are more distantly related and contain no defined protein interaction motifs. KLF proteins have a zinc finger domain, which is a common motif in transcription factors. The most frequently encountered zinc finger motif is the C2H2 type, which allows the domain to fold into a ββα structure. All members of the KLF family have three zinc finger motifs at the carboxyl-terminal ends of the proteins that are highly conserved. Their location within KLF protein structures is shown in Figure 2. The first and second zinc fingers contain 25 amino acids and the third contains 23 amino acids. Each zinc finger recognizes three base pairs in theThe Krüppel-like factor (KLF) family of transcription factors regulates diverse biological processes, including proliferation, differentiation, growth, development, survival, and responses to external stress. Seventeen mammalian KLFs have been identified, and numerous studies have described their basic biology and contributions to human diseases. KLFs are critical regulators of physiological systems such as the cardiovascular, digestive, respiratory, hematological, and immune systems, and are involved in disorders like obesity, cardiovascular disease, cancer, and inflammatory conditions. Additionally, KLFs play an important role in reprogramming somatic cells into induced pluripotent stem (iPS) cells and maintaining the pluripotent state of embryonic stem cells. As research on KLF proteins progresses, new functions and associations with disease are likely to be discovered. This review addresses the current understanding of the biochemical, biological, and pathophysiological functions of KLF family members. KLF proteins are conserved among mammals, with many having homologs in various species. Tissue expression varies, with some family members expressed ubiquitously and others in specific tissues. KLF proteins share homology in their carboxyl-terminal zinc finger domains, allowing them to bind GC-rich sites in gene promoters and enhancers. These structural similarities create overlap in their transcriptional targets. KLF proteins have distinct amino-terminal sequences that provide unique regions for interaction with specific binding partners. Phylogenetic analysis of the 17 human KLFs defines evolutionary distances of individual family members. Structural homologies of KLFs correlate with functional similarities, likely due to homologous protein interaction motifs in amino-terminal domains. Based on functional characteristics, KLF proteins can be divided into three distinct groups: Group 1 (KLFs 3, 8, and 12) serve as transcriptional repressors through interaction with CtBP; Group 2 (KLFs 1, 2, 4, 5, 6, and 7) function as transcriptional activators; and Group 3 (KLFs 9, 10, 11, 13, 14, and 16) have repressor activity through interaction with Sin3A. KLFs 15 and 17 are more distantly related and contain no defined protein interaction motifs. KLF proteins have a zinc finger domain, which is a common motif in transcription factors. The most frequently encountered zinc finger motif is the C2H2 type, which allows the domain to fold into a ββα structure. All members of the KLF family have three zinc finger motifs at the carboxyl-terminal ends of the proteins that are highly conserved. Their location within KLF protein structures is shown in Figure 2. The first and second zinc fingers contain 25 amino acids and the third contains 23 amino acids. Each zinc finger recognizes three base pairs in the