Li-ion batteries are already being used in several applications, from portable devices to the automotive industry, and they represent a promising option also for other critical uses, such as in the storage of energy from renewable sources. However, two of the main concerns that still hinder their massive introduction in these further areas, are their safety and reliability. Depending on cell characteristics and operating conditions, the heat generated within the cell can exceed that dissipated from its surface, and the cell will fail, possibly with catastrophic consequences. To identify the hazardous working conditions of a cell, a simulation model including the main exothermic reactions was set up to investigate the onset of thermal runaway in several Li-ion cell configurations under various operating conditions. The behavior of four different cathodes under thermal abuse and the influence of external factors such as the environmental temperature and the cooling system efficiency were assessed. It was found that among those investigated, the lithium iron phosphate cathode is characterized by a higher thermal stability and that an efficient superficial heat exchange can prevent thermal runaway in most of the cases.