Nonfuctional pituitary neuroendocrine tumor (NF-PitNET) is highly heterogeneous and generally considered a common intracranial tumor. A series of molecules are involved in NF-PitNET pathogenesis that alter in multiple levels of genome, transcriptome, proteome, and metabolome, and those molecules mutually interact to form dynamically associated molecular-network systems. This article reviewed signaling pathway alterations in NF-PitNET based on the analyses of the genome, transcriptome, proteome, and metabolome, and emphasized signaling pathway network alterations based on the integrative omics, including calcium signaling pathway, cGMP-PKG signaling pathway, mTOR signaling pathway, PI3K/AKT signaling pathway, MAPK (mitogen-activated protein kinase) signaling pathway, oxidative stress response, mitochondrial dysfunction, and cell cycle dysregulation, and those signaling pathway networks are important for NF-PitNET formation and progression. Especially, this review article emphasized the altered signaling pathways and their key molecules related to NF-PitNET invasiveness and aggressiveness that are challenging clinical problems. Furthermore, the currently used medication and potential therapeutic agents that target these important signaling pathway networks are also summarized. These signaling pathway network changes offer important resources for insights into molecular mechanisms, discovery of effective biomarkers, and therapeutic targets for patient stratification, predictive diagnosis, prognostic assessment, and targeted therapy of NF-PitNET.