The biological basis of physiological signals is incredibly complex. While many types of research certainly appreciate molecular, cellular and systems approach to unravel overall biological complexity, in the recent decades the interest for mathematical and computational characterization of structural and functional basis underlying biological phenomena gain wide popularity among scientists. Nowadays, we witnessed wide range applications of nonlinear quantitative analysis that produced measures such as fractal dimension, power-law scaling, Hurst exponent, Lyapunov exponent, approximate entropy, sample entropy, Lempel–Ziv complexity, as well as other metrics for predictions of onset and progression of many pathological conditions, especially in the central nervous systems (CNS). In this Research Topic, we seek to bring together the recent practical and theoretical advances in the development and application of nonlinear methods or narrower fractal-based methods for characterizing the complex physiological systems at multiple levels of the organization. We will discuss the use of various complexity measures and appropriate parameters for characterizing the variety of physiological signals up to the systems level. There are multiple aims in this topic. The recent advancement in the application of nonlinear methods for both normal and pathological physiological conditions is the first. The second aim is to emphasize the more recent successful attempt to apply these methods across animal species. Finally, a comprehensive understanding of advantages and disadvantages of each method, especially between its mathematical assumptions and real-world applicability, can help to find out what is at stake regarding the above aims and to direct us toward the more fruitful application of nonlinear measures and statistics in physiology and biology in general.