By means of DFT and AIM calculations, the steric and stereoelectronic effects that control the enantioselectivity in the cross-aldol addition of acetone to isatin catalysed by L-proline have been studied. This reaction results in a reversal of enantioselectivity when compared with the corresponding cross-aldol addition to 4,6-dibromoisatin and to aldehydes. DFT calculations of the cross-aldol transition states indicate that product formation follows different pathways for the substrates isatin and 4,6-dibromoisatin. In the case of isatin, the S-enantiomer is favoured as a consequence of a stereoelectronic effect that results in a lower energy transition state for the S-enantiomer relative to the R- enantiomer. In contrast, the cross-aldol addition of acetone to 4,6-dibromoisatin furnishes the expected R-enantiomer due to a steric effect of the 4-bromo substituent which inhibits formation of the S-enantiomer via the stereoelectronically favoured transition state.