When performing empirical research in public health and medicine, the investigator is typically faced with a variety of methodologic issues to resolve at the design and analysis stages of the research. The investigator must specify the research question, conceptualize and operationalize the variables to be measured, consider several research designs to choose from, determine appropriate measures of disease frequency and effect, address potential biases, devise the analytic strategies to follow, choose the appropriate software procedures or packages to use, carry out the analysis, and interpret the results. Most of these issues concern principles and methods of epidemiology and biostatistics, which, taken together, embody the methodologic "science" that underlies such research. Nevertheless, in bringing all these issues together to achieve a coherent and valid research conclusion, there is an "art" that is required that goes beyond the quantitative mechanics involved in carrying out the research. The art part is not easily quantifiable and typically is more skillfully performed as one becomes a more experienced investigator. Nevertheless, such methodologic art can be addressed methodologically through guidelines that identify the options or strategies available and suggest how appropriate choices can be made from such options or strategies. Selection bias and mathematical modeling are especially addressed.