Amyotrophic lateral sclerosis (ALS) is a lethal neurological disorder that leads to progressive degeneration and loss of motor neurons (MN). Neural progenitor cells derived from the spinal cord have the potential to differentiate into various cell types, including both neurons and glia, within the disease microenvironment. Combining growth factors with Schwann cells, glia, and stem cells delivers both cellular and neurotrophic support. Insulin-like growth factor-I (IGF-I) is a growth factor with neuroprotective properties highly considered for treatment of ALS. The combination of human spinal cord stem cells (HSSC) with IGF-I treatment may provide a systems approach to the treatment of ALS as well as other motor neuropathies. Our hypothesis is that IGF-I in combination HSSC will enhance HSSC integration into the host tissue and offer greater neuroprotection in neurodegenerative diseases. Our goal is to understand the role of IGF-I in stem cell biology and how IGF-I may interact with stem cells to increase their neuroprotective effects. The direct effects of IGF-I on the differentiation of HSSC were assessed either by western blotting or immunocytochemistry. Cell death was assessed using TUNEL. Our findings demonstrate that IGF-I is produced early in HSSC differentiation. Direct treatment with IGF-I does not change the expression profile of HSSC as they are differentiating, suggesting IGF-I does not affect lineage selection, but rather enhances neural development and neurite outgrowth. Signaling via AKT, but not MAPK mediates IGF-I-stimulated neurite outgrowth. HSSC are more resistant to glutamate excitotoxicity than mature MNs. As such, HSSC may be less susceptible to pathogenic factors while they mature; however, IGF-I remains a potent neuroprotective factor for excitotoxic stress in HSSC. Finally, IGF-I does not promote proliferation of HSSC. Our data support the idea that upregulation of IGF-I production in HSSC may offer additional therapeutic benefits when HSSC engineered to overexpress IGF-I are transplanted into the nervous system of animal models and humans with neurological disorders.