Malaria transmission is a multifactorial phenomenon. Climate is a major limiting factor in the spatial and temporal distribution of malaria, but many non-climatic factors may alter or override the effect of climate. Thirty years of monthly malaria incidence data from KwaZulu-Natal province, South Africa, reveal strong medium and long-term trends, which were not present in the climate data. This paper explores various non-climatic factors that may have contributed towards the observed trends. The development of antimalarial drug resistance, available information on human immunodeficiency virus (HIV) prevalence, cross-border people movements, agricultural activities, emergence of insecticide resistance and the case reporting system are reviewed and their potential effect on malaria transmission examined. Single-variable linear regression analysis showed significant association between seasonal case totals (log-transformed) and the measured level of drug resistance (log-transformed) (r2=0.558, n=10, P=0.013) as well as relative measures of HIV infection since 1990 (r2=0.846, n=11, P=0.001). The other factors appear to have affected the level of malaria transmission at certain periods and to some degree. The importance of surveillance and inclusion of non-climatic variables in analysis of malaria data is demonstrated.