Protein kinase cascades feature in many signal transduction pathways. For those discussed here, a single upstream protein kinase appears to be responsible for the control of multiple downstream targets. So how is specificity introduced into these events? For the downstream kinases (substrates) described here, it would appear that specificity is determined by substrate-directed events that are permissive for phosphorylation. There are also distinctions relating to the turnover of these phosphorylations providing a further element of specificity.