A neonate presenting to the emergency department can present a challenge to even the most experienced clinician. This article has focused on four deceiving and potentially devastating neonatal diseases. 1. Neonatal herpes is a potentially devastating illness without pathognomonic signs or symptoms. Early recognition and therapy can reduce mortality markedly. Although no specific sign or symptom is diagnostic,the diagnosis should be strongly considered in the presence of HSV risk factors, atypical sepsis, unexplained acute hepatitis, or focal seizure activity. Acyclovir therapy should be initiated before viral dissemination or significant CNS replication occurs. 2. Pertussis is a disease in which infants are at greatest risk of death or severe complication. Neonatal pertussis often presents in an atypical manner, lacking the classic signs and symptoms such as the "whoop."More common signs and symptoms include cough, feeding difficulty,low-grade fever, emesis, increasing respiratory distress, apnea, cyanosis,and seizures. Management should include hospitalization, supportive care, and antibiotics. 3. Congenital heart defects, particularly ductal-dependent lesions, may have an initial asymptomatic period that culminates in a rapidly progressive and fatal course. A neonate with CHD presents with shock refractory to volume resuscitation or pressor support. Resuscitative efforts are ineffective unless PGE, is administered. 4. Inborn errors of metabolism often are unsuspected because of their protean and heterogeneous nature. Signs and symptoms are subtle,are nonspecific, and often mimic other, more common diseases.An elevated index of suspicion, along with application and correct interpretation of a select few laboratory tests, is the key to making a diagnosis. Therapy is relatively straightforward and focused on resuscitation followed by prevention of catabolism and correction of specifically identified abnormalities. Although these disorders are relatively uncommon, prompt diagnosis and therapy can lead to a decrease in morbidity and mortality. The key is to maintain a high index of suspicion.