The leukocyte common antigen-related (LAR) subfamily of receptor protein tyrosine phosphatases (RPTPs), LAR, RPTP-, and RPTP-␦, regulate neuroendocrine development, axonal regeneration, and hippocampal long-term potentiation in mammals. In Drosophila, RPTPs are required for appropriate axon targeting during embryonic development. In contrast, deletion of any one of the three LAR-RPTP family members in mammals does not result in gross axon targeting defects. Both RPTP-and RPTP-␦ are highly expressed in the developing mammalian nervous system, suggesting they might be functionally redundant. To test this hypothesis, we generated RPTPand RPTP-␦ (RPTP-/␦) double-mutant mice. Although embryonic day 18.5 RPTP-and RPTP-␦ single-mutant embryos were viable, RPTP-/␦ double mutants were paralyzed, were never observed to draw a breath, and died shortly after cesarean section. RPTP-/␦ double mutants exhibit severe muscle dysgenesis and severe loss of motoneurons in the spinal cord. Detailed analysis of the projections of phrenic nerves in RPTP-/␦ double mutants indicated that these motoneuron axons emerge normally from the cervical spinal cord, but stall on reaching the diaphragm. Our results demonstrate that RPTP-and RPTP-␦ complement each other functionally during mammalian development, and reveal an essential contribution of RPTP-and RPTP-␦ to appropriate motoneuron axon targeting during mammalian axonogenesis.