Current antifungal pharmaceuticals do not actively kill fungi; their fungistatic activity simply prevents the growth and spread of an infection. However, these compounds can be turned fungicidal and actively kill fungal cells by the simultaneous pharmacological inhibition of calcineurin in the Ca²⁺-signaling pathway. However, calcineurin is crucial for the activation of the human immune response, so combinatorial drug therapy carries too much risk of a bacterial opportunistic infection. The research in this dissertation expands our understanding of the relationship between azole antifungals and the Ca²⁺-signaling pathway by identifying the calmodulin-dependent kinase Cmk2, but not its homolog Cmk1, as an additional component of the Ca²⁺-signaling pathway necessary to prevent cell death for azole- or Tunicamycin-derived ER stress. We have also identified a complex mechanism in the Ca²⁺-signaling network where Tcn1, the transcription factor immediately downstream of calcineurin, functions to activate Cmk2. Calcineurin and Cmk2 appear to function in a somewhat redundant manner to prevent cell death. Finally, we have also identified the ER membrane bound calcineurin target Hph1 (and its non-target homolog Hph2), as critical in preventing cell death in response to azole class antifungals. In addition to the above work, we have refined the use of TUNEL and ROS assays; and discounted the use of fluorescent caspase assays for the field of yeast apoptosis. Finally, we have demonstrated that, despite claims to the contrary, the cell death from synthetic azole class or natural Tunicamycin antifungals coupled with an impaired Ca²⁺-signaling network is not apoptotic in nature.