The WNT-β-catenin pathway is crucial for development, tissue homeostasis, and regeneration, but its aberrant regulation is linked to various diseases, including cancer, fibrosis, and neurodegeneration. Despite this, therapeutic agents targeting the WNT pathway have only recently entered clinical trials, with none yet approved. The pathway is complex, involving 19 ligands, over 15 receptors, and multiple signaling cascades, making it challenging to develop safe and effective therapeutics. Both canonical and non-canonical WNT signaling exist, with the former involving β-catenin and the latter being β-catenin-independent. The pathway plays a key role in cancer, neurological diseases, osteoporosis, fibrosis, and aging. While WNT signaling is essential for tissue repair and regeneration, its dysregulation can lead to disease. Therapeutic strategies targeting WNT signaling must balance its roles in stem cell maintenance, tissue homeostasis, and disease progression. Challenges include the complexity of the pathway, potential off-target effects, and the need for personalized approaches. Recent advances include small-molecule inhibitors and monoclonal antibodies targeting specific components of the WNT pathway, with some in clinical trials. However, long-term safety and efficacy remain concerns, particularly in chronic conditions. The WNT pathway's involvement in multiple diseases highlights the need for careful modulation to avoid unintended consequences.The WNT-β-catenin pathway is crucial for development, tissue homeostasis, and regeneration, but its aberrant regulation is linked to various diseases, including cancer, fibrosis, and neurodegeneration. Despite this, therapeutic agents targeting the WNT pathway have only recently entered clinical trials, with none yet approved. The pathway is complex, involving 19 ligands, over 15 receptors, and multiple signaling cascades, making it challenging to develop safe and effective therapeutics. Both canonical and non-canonical WNT signaling exist, with the former involving β-catenin and the latter being β-catenin-independent. The pathway plays a key role in cancer, neurological diseases, osteoporosis, fibrosis, and aging. While WNT signaling is essential for tissue repair and regeneration, its dysregulation can lead to disease. Therapeutic strategies targeting WNT signaling must balance its roles in stem cell maintenance, tissue homeostasis, and disease progression. Challenges include the complexity of the pathway, potential off-target effects, and the need for personalized approaches. Recent advances include small-molecule inhibitors and monoclonal antibodies targeting specific components of the WNT pathway, with some in clinical trials. However, long-term safety and efficacy remain concerns, particularly in chronic conditions. The WNT pathway's involvement in multiple diseases highlights the need for careful modulation to avoid unintended consequences.