The LHX3 LIM-homeodomain transcription factor is critical for the development of the mammalian pituitary gland and its hormone-secreting cells as well as for parts of the nervous system, including roles in the specification of motor neurons^[1][2]. LHX3 is part of a regulatory program of transcription factors that regulate the determination and differentiation of anterior pituitary cell types (Figure 1). The human and mouse LHX3 genes each have seven coding exons (Figure 2)^[3] that generate two major mRNA transcripts (LHX3a, LHX3b)^[4][5][6] from two upstream promoters^[7]. The LHX3 mRNAs encode three protein isoforms: LHX3a, LHX3b, and M2-LHX3^[5][6]. The zinc-coordinated LIM domains allow LHX3 to interact with other transcription factors and with regulatory proteins. The DNA-binding homeodomain mediates interaction with cis-acting transcription regulatory regions in target genes. Recessive mutations in the LHX3 gene are associated with combined pituitary hormone deficiency (CPHD) and other features including a rigid cervical spine and deafness (Figure 3)^[1]. Deficiencies in growth hormone, luteinizing hormone, follicle-stimulating hormone, prolactin, and thyroid-stimulating hormone result in short stature, metabolic disease, and reproductive problems for patients with LHX3 gene mutations^{[8][9][10][11][12][13][14]}