Cytotoxic T lymphocytes (CTLs) kill targets by releasing cytotoxic agents from lytic granules. Killing is a multi‐step process. The CTL adheres to a target, allowing its T‐cell receptors to recognize antigen. This triggers a signal transduction cascade that leads to the polarization of the microtubule cytoskeleton and granules towards the target, followed by exocytosis that occurs specifically at the site of contact. As with cytokine production by helper T cells (Th cells), target cell killing is absolutely dependent on Ca²⁺ influx, which is involved in regulating both reorientation and release. Current evidence suggests that Ca²⁺ influx in CTLs, as in Th cells, occurs via depletion‐activated channels. The molecules that couple increases in Ca²⁺ to reorientation are unknown. The Ca²⁺/calmodulin‐dependent phosphatase calcineurin, which plays a critical role in cytokine production by Th cells, is also involved in lytic granule exocytosis, although the relevant substrates remain to be identified and calcineurin activation is only one Ca²⁺ ‐dependent step involved. There are thus striking similarities and important differences between Ca²⁺ signals in Th cells and CTLs, illustrating how cells can use similar signal transduction pathways to generate different functional outcomes.