...and your 100% sure your xpath is correct. It's probably that there is a namespace defined. All you need to do is define the namespace under the xmlpoke element and prefix your element names with the namespace prefix. Check it:

web.config:

<configuration xmlns="http://schemas.microsoft.com/.NetConfiguration/v2.0">
  <appSettings>
    <add key="SomeSetting" value="" />
  </appSettings>
</configuration>

NAnt:

<project name="YadaYadaYada" default="default">
    <target name="default">
        <xmlpoke
             file="D:\Temp\web.config"
             xpath="/ns:configuration/ns:appSettings/ns:add[@key='SomeSetting']/@value"
             value="SomeValue">
                  <namespaces>
                      <namespace prefix="ns" uri="http://schemas.microsoft.com/.NetConfiguration/v2.0" />
                  </namespaces>
         </xmlpoke>
   </target>
</project>