Progressive neuronal loss is a hallmark of many neurodegenerative diseases, including Alzheimer's and Parkinson's disease. These pathologies exhibit clear signs of inflammation, mitochondrial dysfunction, calcium deregulation, and accumulation of aggregated or misfolded proteins. Over the last decades, a tremendous research effort has contributed to define some of the pathological mechanisms underlying neurodegenerative processes in these complex brain neurodegenerative disorders. To better understand molecular mechanisms responsible for neurodegenerative processes and find potential interventions and pharmacological treatments, it is important to have robust in vitro and pre-clinical animal models that can recapitulate both the early biological events undermining the maintenance of the nervous system and early pathological events. In this regard, it would be informative to determine how different inherited pathogenic mutations can compromise mitochondrial function, calcium signaling, and neuronal survival. Since post-mortem analyses cannot provide relevant information about the disease progression, it is crucial to develop model systems that enable the investigation of early molecular changes, which may be relevant as targets for novel therapeutic options. Thus, the use of human induced pluripotent stem cells (iPSCs) represents an exceptional complementary tool for the investigation of degenerative processes. In this review, we will focus on two neurodegenerative diseases, Alzheimer's and Parkinson's disease. We will provide examples of iPSC-derived neuronal models and how they have been used to study calcium and mitochondrial alterations during neurodegeneration.