The presence of long-range correlations and/or mosaicism in DNA sequences results in GC fluctuations, even within individual isochores that are much larger than expected correlation-free 'random' sequences. Neglecting the presence of such fluctuations can lead to incorrect conclusions regarding relative homogeneity or isochore borders. In this commentary, we address these and other methodological issues raised by the variations in GC level within human isochores. We also discuss some recent misconceptions.