Thrombocytopenia is a very frequent problem among sick neonates, affecting up to 35% of all infants admitted to the NICU. Although multiple clinical conditions have been causally associated with neonatal thrombocytopenia, the cause of the thrombocytopenia is unclear in up to 60% of affected neonates. This article provides neonatologists with a practical approach to the thrombocytopenic neonate, with an emphasis on conditions that could be life-threatening or could have significant implications for further pregnancies. An overview of the current therapeutic modalities is also presented, including a discussion of the possible use of recombinant thrombopoietic cytokines to treat certain groups of thrombocytopenic neonates.