Schizophrenia (SZ), a pervasive psychiatric disorder, continues to be associated with high economic costs, high rates of disability, and premature mortality despite the widespread use of antipsychotic drugs. Clearly, a deeper understanding of the molecular disruptions associated with this disorder is warranted. Alterations in brain energy metabolism leading to increased lactate and acidity are increasingly associated with and may even contribute to the development of SZ. Intracellular organelles responsible for protein posttranslational modifications (PTMs) and trafficking are quite sensitive to pH alterations, and deficits in protein PTMs and trafficking are well documented in SZ brain. This chapter will explore the implications of increased brain acidity in SZ as well as the proteins involved in regulating intracellular pH with a particular focus on organellar Na+/H+ exchangers (NHEs), which are major regulators of pH in intracellular organelles heavily responsible for protein modification and trafficking such as Golgi and endosomes. This chapter will also discuss how alterations in organellar NHEs may underlie well-known deficits in protein modification and trafficking in SZ brain and could serve as effective targets for future SZ therapeutics.