Hepatitis C variability is a field of numerous investigations. Information drawn from these studies is useful for a better comprehension of hepatitis C virus-related disease and for development of new preventive or therapeutic tools. With this aim, a critical analysis of viral quasispecies obtained by cloning and sequencing needs to follow some recommendations. From extraction procedure of high quality with careful conservation of RNA extracts, results should be obtained by reliable RT-PCR systems with random and/or degenerated primers in order to avoid any possible selection bias. The recommendations are exposed and discussed in detail to obtain reliable experimental data for valid biological findings.