Understanding the frequency with which new resistance alleles arise and their subsequent patterns of spread is critical to our attempts to manage drug resistance in parasite populations. We review recent molecular evolutionary studies utilizing marker loci situated close to resistance loci on the Plasmodium falciparum genome that have given surprising insights into the origins and spread of drug resistance loci. We discuss possible reasons for the patterns observed, and highlight the implications of these results for resistance management. In particular, we show that many resistance mutations have rather few independent origins. De novo mutation appears to be less important than migration for introducing resistance alleles into parasite populations. Attempts to manage drug resistance will be of limited effectiveness unless this is taken into account.